Dopamine-b-hydroxylase inhibitors

ABSTRACT

This invention relates to: (a) compounds of formula Ia (with R1, R4 to R6, n and A as defined herein) and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-p-hydroxylase inhibitors; (b) pharmaceutical compositions (comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds.

FIELD OF THE INVENTION

This invention relates to: (a) compounds and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-β-hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; and (d) therapeutic methods of treatment using such compounds, salts or solvates.

BACKGROUND OF THE INVENTION

The enzyme dopamine-β-hydroxylase (DβH), also known as dopamine β-monooxygenase, is expressed both in the periphery and the central nervous system (CNS). DβH catalyses the specific hydroxylation of dopamine (DA) to produce norepinephrine, also known as noradrenaline (NA). As such, inhibitors of DβH can inhibit the biosynthesis of NA, limiting its concentration and increasing DA levels.

In recent years, interest in the development of inhibitors of DβH has centred on the hypothesis that inhibition of this enzyme may provide significant clinical improvements in patients suffering from cardiovascular disorders such as hypertension or chronic heart failure. The rationale for the use of DβH inhibitors is based on their capacity to inhibit the biosynthesis of NA, which is achieved via enzymatic hydroxylation of DA. Reduction of the biosynthesis of NA via inhibition of DβH can directly dampen sympathetic nerve function, the activation of which is the principal clinical manifestation of congestive heart failure (Parmley, W. W., Clin. Cardiol., 18: 440-445, 1995). Congestive heart failure patients have elevated concentrations of plasma noradrenaline (Levine, T. B. et al., Am. J. Cardiol., 49:1659-1666, 1982), increased central sympathetic outflow (Leimbach, W. N. et al., Circulation, 73: 913-919, 1986) and augmented cardiorenal noradrenaline spillover (Hasking, G. J. et al., Circulation, 73:615-621, 1966). Prolonged and excessive exposure of the myocardium to noradrenaline may lead to down-regulation of cardiac β₁-adrenoceptors, remodelling of the left ventricle, arrhythmias and necrosis, all of which can diminish the functional integrity of the heart. Congestive heart failure patients who have high plasma concentrations of noradrenaline also have the most unfavourable long-term prognosis (Cohn, J. N. et al., N. Engl. J. Med., 311:819-823, 1984). Of greater significance is the observation that plasma noradrenaline concentrations are already elevated in asymptomatic patients with no overt heart failure and can predict ensuing mortality and morbidity (Benedict, C. R. et al., Circulation, 94:690-697, 1996). An activated sympathetic drive is not therefore merely a clinical marker of congestive heart failure, but may contribute to progressive worsening of the disease.

DβH inhibitors may also display activity the CNS, if they cross the blood-brain barrier (BBB).

Several inhibitors of DβH have been thus far reported in the literature. Early first and second generation examples such as disulfiram (Goldstein, M. et al., Life Sci., 3:763, 1964) and diethyldithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol., 18: 2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and aromatic or alkyl thioureas (Johnson, G. A. et al, J. Pharmacol. Exp. Ther., 171: 80, 1970) were found to be of low potency, exhibited poor selectivity for DβH and caused toxic side effects. The third generation of DβH inhibitors, however, were found to have much greater potency, such as, for example, nepicastat (RS-25560-197, IC₅₀ 9 nM) (Stanley, W. C., et al., Br. J. Pharmacol., 121: 1803-1809, 1997), which was developed to early clinical trials. Although it was initially developed for peripheral indications (hypertension and congestive heart failure), an important discovery was that nepicastat was found to cross the BBB, and was thereby able to cause central as well as peripheral effects.

Nepicastat and its analogues are disclosed in WO95/29165. Furthermore, WO 2004/033447 and WO 2008/136695 disclose DβH inhibitors having high potency and significantly reduced brain access, giving rise to potent and peripherally selective DβH inhibitors. However, these compounds are also difficult to synthesise requiring many steps in the synthetic route making them expensive to manufacture. In particular, potent compounds disclosed in WO 2008/136695 are sparingly soluble and display improved levels of exposure when administered with high-fat meals. A review of the mechanism, substrates and inhibitors of DβH, is given by Beliaev, A., et al. in Current Enzyme Inhibition, 5, 27-43, 2009.

WO2018/056854 and WO2018/056855 disclose DβH inhibitors which are useful for the treatment of conditions ameliorated by inhibition of DβH within the CNS. Compared with the compounds of formula Ia of the present invention, the compounds of WO2018/056854 and WO2018/056855 have different substituents at position R₆. In addition, the sub-headings to Step 3 of Example 80 of WO2018/056854 and Step 3 of Example 3 of WO2018/056855 incorrectly disclose the chemical name (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione instead of the actual compound name (S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione (emphasis added).

Therefore, there remains an unfulfilled clinical requirement for a potent, non-toxic and peripherally selective inhibitor of DβH, which could be used for treatment of certain cardiovascular disorders. A DβH inhibitor with similar or even greater potency than nepicastat, but devoid of CNS effects (i.e. unable to efficiently cross the BBB), yet exhibiting a long residence time in the periphery so as to provide a long duration of DβH inhibition would provide a significant improvement over all DβH inhibitor compounds thus far described in the prior art. Additionally, such compounds would preferably be orally bioavailable, highly soluble and easier and cheaper to synthesise.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof:

wherein: R₁ is hydrogen, C₁-C₆ alkyl, partially or fully deuterated C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₄ is hydrogen or C₁-C₃ alkyl; R₅ is hydrogen; or R₄ and R₅ combine, together with the carbon atoms to which they are attached, to form a cyclopropyl ring; R₆ is —COOH, —CHO, or —(CH₂)_(m)—X,

-   -   wherein:     -   m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may         optionally be replaced by

-   -   X is hydroxy, C₁-C₃ alkoxy, cyano, —N═CH(NHCN)(NH₂),         —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl         optionally substituted with one methyl group, phenyl, —SO₂—R₇,         —NR₈R₉,     -   —CO₂R₁₀, —CH(CO₂R₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;         -   wherein:         -   R₇ is C₁-C₃ alkyl;         -   R₈ is hydrogen or C₁-C₃ alkyl;         -   R₉ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of hydroxy, methylsulfonyl,                 C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl                 and 5- or 6-membered heteroaryl optionally substituted                 with one methyl substituent,             -   C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents;         -   or R₈ and R₉ combine together with the N atom to which they             are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from methyl,                 trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl,                 methylsulfonyl, amido, (N,N-dimethyl)acetamide and                 pyridyl or with one or two substituents selected from                 fluoro and oxo, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₀ is hydrogen or C₁-C₃ alkyl;         -   R₁₁ is hydrogen or C₁-C₃ alkyl;         -   R₁₂ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of cyano, hydroxy,                 methylsulfonyl, C₁-C₂ alkoxy, dimethylamino, C₃-C₆                 cycloalkyl, phenyl, 5- or 6-membered heteroaryl                 optionally substituted with one methyl substituent and                 5- or 6-membered heterocyclyl optionally substituted                 with one t-Boc group or with one or two fluoro                 substituents,             -   C₃-C₆ cycloalkyl optionally substituted with one                 substituent selected from the group consisting of cyano,                 hydroxy, hydroxymethyl and oxo, cyano,             -   methylsulfonyl,             -   CH₂COO(C₁-C₃ alkyl),             -   5- or 6-membered heteroaryl optionally substituted with                 one methyl substituent,             -   4-, 5- or 6-membered heterocyclyl optionally substituted                 with one or two substituents selected from oxo and                 methyl,             -   CH₂CH(NH₂)(COOH), or             -   CH(CH₃)CONH₂;         -   or R₁₁ and R₁₂ combine together with the N atom to which             they are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from                 monofluoromethyl, trifluoromethyl, hydroxy,                 hydroxymethyl, methoxymethyl, methylsulfonyl, cyano,                 amido, (N,N-dimethyl)acetamide and pyridyl, or with one                 or two substituents selected from fluoro, methyl and                 oxo, or optionally fused to a cyclopropyl ring which may                 be substituted with one or two methyl substituents, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₃ is hydrogen or C₁-C₃ alkyl;         -   R₁₄ is C₁-C₄ alkyl optionally substituted with up to three             fluoro substituents or with one substituent selected from             the group consisting of hydroxy, methylsulfonyl, C₃-C₆             cycloalkyl and phenyl, C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents;                 A is C₅-C₇ cycloalkyl, furanyl, thiophenyl,                 methylthiophenyl or

-   -   wherein:     -   X₁ is hydrogen, halo or methyl;     -   X₁′ is hydrogen or halo;     -   X₂ is hydrogen, halo or methyl;     -   X₂′ is hydrogen or halo;     -   X₃ is hydrogen or fluoro;         n is 0 or 1, and when n is 0 a single bond joins the carbon         atoms to which the CH₂ moiety would be attached when n is 1.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a method for treating or preventing conditions ameliorated by inhibition of DβH outside the CNS comprising administering a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

This invention is also directed to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione is excluded.

Certain compounds of formula Ia may exist as tautomers. Where tautomers exist, each tautomeric form, and mixtures thereof, are contemplated as included in the present invention. Any reference in this specification to one specific tautomer of a compound of formula Ia is understood to encompass every tautomeric form as well as any mixtures thereof, in any ratio. The same applies to tautomers of more specific embodiments of compounds of formula Ia described herein, such as, but not limited to, tautomers of compounds of formula Ib, Ic, Id, Ie, If, Ig, Ih, Ii and Ij described below, and tautomers of the specific examples described in the experimental section below.

DETAILED DESCRIPTION OF THE EMBODIMENTS A. Definitions

“C₁-C₆ alkyl” means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms. “C₁-C₂ alkyl”, “C₁-C₃ alkyl”, “C₁-C₄ alkyl” and “C₁-C₅ alkyl” have analogous meanings.

“partially or fully deuterated C₁-C₆ alkyl” means a C₁-C₆ alkyl wherein some or all of the hydrogen atoms have been replaced by deuterium.

“C₃-C₆ cycloalkyl” means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms. “C₅-C₇ cycloalkyl” has analogous meaning.

“C₁-C₃ alkoxy” means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon having from 1 to 3 carbon atoms connected to the rest of the compound of formula Ia via a single oxygen atom. “C₁-C₂ alkoxy” has analogous meaning.

“5- or 6-membered heteroaryl” means a monocyclic aromatic group with a total of 5 atoms in the ring wherein from 1 to 4 of those atoms are each independently selected from N, O and S; or a monocyclic aromatic group with a total of 6 atoms in the ring wherein from 1 to 3 of those atoms are N. 5-membered heteroaryl groups include pyrrolyl (also called azolyl), furanyl, thienyl (also called thiophenyl), pyrazolyl (also called 1H-pyrazolyl and 1,2-diazolyl), imidazolyl, oxazolyl (also called 1,3-oxazolyl), isoxazolyl (also called 1,2-oxazolyl), thiazolyl (also called 1,3-thiazolyl), isothiazolyl (also called 1,2-thiazolyl), triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl and thiatriazolyl. 6-membered heteroaryl groups include pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl and triazinyl.

“4-, 5- or 6-membered heterocyclyl” means a saturated monocyclic group with a total of 4 atoms in the ring wherein 1 of those atoms is selected from N, O and S; or a saturated monocyclic group with a total of 5 atoms in the ring wherein 1 or 2 of those atoms are each independently selected from N, O and S; or a saturated monocyclic group with a total of 6 atoms in the ring wherein 1 or 2 of those atoms are each independently selected from N, O and S. 4-membered heterocyclyl groups include azetidine, oxetane and thietane. 5-membered heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl (also called terahydrothiophenyl), imidazolidinyl, pyrazolidinyl, dioxolanyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and isothiazolidinyl. 6-membered heterocyclyl groups include piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl and thiomorpholinyl.

“5- or 6-membered N-heterocyclyl” means a saturated monocyclic group with a total of 5 atoms in the ring wherein 1 of those atoms is N and another one of those atoms is optionally selected from N, O and S; or a saturated monocyclic group with a total of 6 atoms in the ring wherein 1 of those atoms is N and another one of those atoms is optionally independently selected from N, O and S. 5-membered N-heterocyclyl groups include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and isothiazolidinyl. 6-membered N-heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

“9- or 10-membered heterospirocyclyl” means a saturated spirocyclic group with a total of 9 atoms in the two rings wherein from 1 to 4 of those atoms are each independently selected from N, O and S; or a saturated spirocyclic group with a total of 10 atoms in the two rings wherein from 1 to 5 of those atoms are each independently selected from N, O and S. 9-membered heterospirocyclyl groups include 2-oxa-7-azaspiro[4.4]nonanyl. 10-membered heterospirocyclyl groups include 2-oxa-8-azaspiro[4.5]decanyl and 1,4-dioxa-8-azaspiro[4.5]decanyl.

“oxo” means an oxo radical, and may be depicted as ═O.

“halo” means a fluorine (which may be depicted as —F), chlorine (which may be depicted as —Cl), bromine (which may be depicted as —Br) or iodine (which may be depicted as —I) radical.

“amido” means —CONH₂.

“t-Boc” means tert-butyloxycarbonyl.

“pharmaceutically acceptable salt” means a salt such as those described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH, 2002), or S. M. Berge, et al., “Pharmaceutical Salts” (1977) Journal of Pharmaceutical Sciences, 66, 1-19.

“pharmaceutically acceptable solvate” means a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. The term “hydrate” maybe employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

“pharmaceutically acceptable excipient” means any ingredient other than the compound(s) of the invention, or other known pharmacologically active components. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

“therapy”, “treatment” and “treating” include both preventative and curative treatment of a condition, disease or disorder. It also includes slowing, interrupting, controlling or stopping the progression of a condition, disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a condition, disease or disorder.

Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

B. Compounds

The invention provides a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof:

The invention also provides a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione is excluded.

B0. Core Structures

In some embodiments of formula Ia, n is 0 and a single bond joins the carbon atoms to which the CH₂ moeity would be attached when n is 1 to form a structure of formula Ib

In some embodiments of formula Ia, R₄ and R₅ combine, together with the carbon atom to which they are attached, to form a structure of formula Ic:

In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R₅ and A of compounds of formula Ia have the stereochemical configuration of formula Id

In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R₅ and A of compounds of formula Ia have the stereochemical configuration of formula Ie

Preferred embodiments of formula Ia include compounds of formula If.

In some particularly preferred embodiments of formula If more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R₅ and A of compounds of formula If have the stereochemical configuration of formula Ig

In other more particularly preferred embodiments of formula If more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R₅ and A of compounds of formula If have the stereochemical configuration of formula Ih

More preferred embodiments of formula Ia include compounds of formula Ii.

In some particularly preferred embodiments of formula Ii more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% have the stereochemical configuration of formula Ij.

B1. Substituent R₁

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl, partially or fully deuterated C₁-C₆ alkyl or C₃-C₆ cycloalkyl.

R₁ is preferably selected from the group consisting of hydrogen, C₁-C₆ alkyl and partially or fully deuterated C₁-C₆ alkyl.

In some embodiments R₁ is hydrogen.

In some embodiments R₁ is C₁-C₆ alkyl.

In some embodiments R₁ is partially deuterated C₁-C₆ alkyl.

In some embodiments R₁ is fully deuterated C₁-C₆ alkyl.

In some embodiments R₁ is C₃-C₆ cycloalkyl.

R₁ is preferably selected from the group consisting of hydrogen, methyl, d3-methyl, propyl and cyclopropyl.

R₁ is more preferably selected from the group consisting of hydrogen, methyl and d3-methyl.

In some embodiments R₁ is preferably hydrogen.

In some embodiments R₁ is preferably methyl.

In some embodiments R₁ is preferably d3-methyl.

R₁ is most preferably hydrogen or methyl.

B2. Substituent R₄ (when not Combined with R₅)

R₄ is selected from the group consisting of hydrogen and C₁-C₃ alkyl.

In some embodiments R₄ is hydrogen.

In some embodiments R₄ is C₁-C₃ alkyl.

R₄ is preferably selected from the group consisting of hydrogen and methyl.

In some embodiments R₄ is preferably hydrogen.

In some embodiments R₄ is preferably methyl.

R₄ is most preferably hydrogen.

B3. Substituent R₅ (when not Combined with R₄)

R₅ is hydrogen.

B4. Substituent R₆

R₆ is selected from the group consisting of —COOH, —CHO, or —(CH₂)_(m)—X,

wherein:

-   -   m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may         optionally be replaced by

-   -   X is hydroxy, C₁-C₃ alkoxy, cyano, —N═CH(NHCN)(NH₂),         —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl         optionally substituted with one methyl group, phenyl, —SO₂—R₇,         —NR₈R₉, —CO₂R₁₀, —CH(CO₂R₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;         -   wherein:         -   R₇ is C₁-C₃ alkyl;         -   R₈ is hydrogen or C₁-C₃ alkyl;         -   R₉ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of hydroxy, methylsulfonyl,                 C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl                 and 5- or 6-membered heteroaryl optionally substituted                 with one methyl substituent,             -   C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents;         -   or R₈ and R₉ combine together with the N atom to which they             are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from methyl,                 trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl,                 methylsulfonyl, amido, (N,N-dimethyl)acetamide and                 pyridyl or with one or two substituents selected from                 fluoro and oxo, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₀ is hydrogen or C₁-C₃ alkyl;         -   R₁₁ is hydrogen or C₁-C₃ alkyl;         -   R₁₂ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of cyano, hydroxy,                 methylsulfonyl, C₁-C₂ alkoxy, dimethylamino, C₃-C₆                 cycloalkyl, phenyl, 5- or 6-membered heteroaryl                 optionally substituted with one methyl substituent and                 5- or 6-membered heterocyclyl optionally substituted                 with one t-Boc group or with one or two fluoro                 substituents,             -   C₃-C₆ cycloalkyl optionally substituted with one                 substituent selected from the group consisting of cyano,                 hydroxy, hydroxymethyl and oxo, cyano,             -   methylsulfonyl,             -   CH₂COO(C₁-C₃ alkyl),             -   5- or 6-membered heteroaryl optionally substituted with                 one methyl substituent,             -   4-, 5- or 6-membered heterocyclyl optionally substituted                 with one or two substituents selected from oxo and                 methyl, CH₂CH(NH₂)(COOH), or             -   CH(CH₃)CONH₂;         -   or R₁₁ and R₁₂ combine together with the N atom to which             they are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from                 monofluoromethyl trifluoromethyl, hydroxy,                 hydroxymethyl, methoxymethyl, methylsulfonyl, cyano,                 amido, (N,N-dimethyl)acetamide and pyridyl, or with one                 or two substituents selected from fluoro, methyl and                 oxo, or optionally fused to a cyclopropyl ring which may                 be substituted with one or two methyl substituents, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₃ is hydrogen or C₁-C₃ alkyl;         -   R₁₄ is C₁-C₄ alkyl optionally substituted with up to three             fluoro substituents or with one substituent selected from             the group consisting of hydroxy, methylsulfonyl, C₃-C₆             cycloalkyl and phenyl, C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents.

In one embodiment R₆ is as defined above with the proviso that R₉ may not be 5- or 6-membered heterocyclyl.

In another embodiment R₆ is —COOH, —CHO, or —(CH₂)_(m)—X,

wherein:

-   -   m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may         optionally be replaced by

-   -   X is hydroxy, C₁-C₃ alkoxy, cyano, —N═CH(NHCN)(NH₂),         —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl         optionally substituted with one methyl group, phenyl, —SO₂—R₇,         —NR₈R₉, —CO₂R₁₀, —CH(CO₂R₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;         -   wherein:         -   R₇ is C₁-C₃ alkyl;         -   R₈ is hydrogen or C₁-C₃ alkyl;         -   R₉ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of hydroxy, methylsulfonyl,                 C₃-C₆ cycloalkyl and phenyl, C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents;         -   or R₈ and R₉ combine together with the N atom to which they             are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from methyl,                 trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl,                 methylsulfonyl, amido, (N,N-dimethyl)acetamide and                 pyridyl or with one or two substituents selected from                 fluoro and oxo, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₀ is hydrogen or C₁-C₃ alkyl;         -   R₁₁ is hydrogen or C₁-C₃ alkyl;         -   R₁₂ is hydrogen,             -   C₁-C₄ alkyl optionally substituted with up to three                 fluoro substituents or with one substituent selected                 from the group consisting of cyano, hydroxy,                 methylsulfonyl, C₁-C₂ alkoxy, dimethylamino, C₃-C₆                 cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 5-                 or 6-membered heterocyclyl optionally substituted with                 one t-Boc group or with one or two fluoro substituents,             -   C₃-C₆ cycloalkyl optionally substituted with one                 substituent selected from the group consisting of cyano,                 hydroxy, hydroxymethyl and oxo, cyano,             -   methylsulfonyl,             -   CH₂COO(C₁-C₃ alkyl),             -   5- or 6-membered heteroaryl,             -   5- or 6-membered heterocyclyl optionally substituted                 with one or two oxo substituents,             -   CH₂CH(NH₂)(COOH), or             -   CH(CH₃)CONH₂;         -   or R₁₁ and R₁₂ combine together with the N atom to which             they are attached to form a             -   5- or 6-membered N-heterocyclyl group optionally                 substituted with one substituent selected from methyl,                 trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl,                 methylsulfonyl, amido, (N,N-dimethyl)acetamide and                 pyridyl, or with one or two substituents selected from                 fluoro and oxo, or a             -   9- or 10-membered heterospirocyclyl group;         -   R₁₃ is hydrogen or C₁-C₃ alkyl;         -   R₁₄ is C₁-C₄ alkyl optionally substituted with up to three             fluoro substituents or with one substituent selected from             the group consisting of hydroxy, methylsulfonyl, C₃-C₆             cycloalkyl and phenyl, C₃-C₆ cycloalkyl,             -   5- or 6-membered heteroaryl, or         -   5- or 6-membered heterocyclyl optionally substituted with             one or two oxo substituents.

In some embodiments R₆ is —COOH.

In some embodiments R₆ is —CHO.

In some embodiments R₆ is —(CH₂)_(m)—X wherein m and X are as defined above.

R₆ is preferably —(CH₂)_(m)—X wherein m and X are as defined above.

In some preferred embodiments R₆ is —CH₂—X wherein X is as defined above.

In some preferred embodiments R₆ is —CH₂CH₂—X wherein X is as defined above.

In some preferred embodiments R₆ is —CH₂CH₂CH₂—X wherein X is as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— is replaced by

and X is as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is hydroxy.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is C₁-C₃ alkoxy.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is cyano.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —N═CH(NHCN)(NH₂) or —NH—C(pyrrolidin-1-yl)=NCN.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is 5- or 6-membered heteroaryl optionally substituted with one methyl group.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is phenyl.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —SO₂—R₇ wherein R₇ is as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —NR₈R₉ wherein R₈ and R₉ are as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —CO₂R₁₀ wherein R₁₀ is as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —CH(CO₂R₁₀)₂ wherein R₁₀ is as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —CONR₁₁R₁₂ wherein R₁₁ and R₁₂ are as defined above.

In some preferred embodiments R₆ is —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is —NR₁₃COR₁₄ wherein R₁₃ and R₁₄ are as defined above.

R₆ is preferably —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within (CH₂)_(m)— may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;

wherein:

-   -   R₇ is methyl;     -   R₈ is hydrogen or methyl;     -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,         2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,         1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl,         cyclopentyl, tetrahydrofuran-3-yl, (tetrahydrofuran-2-yl)methyl,         (1,1-dioxido)tetrahydrothiopyran-4-yl,         (tetrahydro-2H-pyran-4-yl)methyl, pyridin-2-yl, pyridin-3-yl,         tetrahydropyran-3-yl, cyclohexyl, (pyridin-2-yl)methyl or         (1-methylpyrazol-4-yl)methyl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a pyrrolidinyl, piperidinyl,         4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or         morpholinyl group; R₁₀ is hydrogen, methyl or ethyl;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl,         (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,         (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl,         2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl,         2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,         2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,         3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl,         cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl,         2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl,         2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl,         4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt,         tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl,         tetrahydropyran-3-yl, tetrahydropyran-4-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl,         pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH), CH(CH₃)CONH₂,         oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl,         (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl,         thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl,         isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,         (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl,         1-methylpyrazol-4-yl, isothiazol-4-yl,         1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl,         1-methyl-5-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl;     -   or R₁₁ and R₁₂ combine together with the N atom to which they         are attached to form a pyrrolidinyl,         2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl,         2-trifluoromethyl-pyrrolidinyl, 3-(fluoromethyl)pyrrolidinyl,         3-methylsulfonyl-pyrrolidinyl,         N,N-dimethylpyrrolidinyl-3-carboxamide, isoxazolidin-2-yl,         piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,         4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,         4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,         4,4-difluoro-piperidinyl, N,N-dimethylpiperidinyl-4-carboxamide,         N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl,         N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,         1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,         2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl,         1,4-dioxa-8-azaspiro[4.5]decanyl group,         6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl,         3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl,         2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl,         3-fluoromethylpyrrolidinyl or         3-(N,N-dimethylacetamide)pyrrolidinyl;     -   R₁₃ is hydrogen or methyl; and     -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,         tetrahydropyran-4-yl or pyridin-3-yl.     -   R₆ is preferably —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one         —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;

-   -   wherein:     -   R₇ is methyl;     -   R₈ is hydrogen or methyl;     -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,         2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,         1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl,         cyclopentyl, tetrahydrofuran-3-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl,         pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl,         (pyridin-2-yl)methyl or (1-methylpyrazol-4-yl)methyl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a pyrrolidinyl, piperidinyl,         4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or         morpholinyl group;     -   R₁₀ is hydrogen, methyl or ethyl;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl,         (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,         (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl,         2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl,         2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,         2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,         3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl,         cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl,         2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl,         2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl,         4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt,         tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl,         tetrahydropyran-3-yl, tetrahydropyran-4-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl,         pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH), CH(CH₃)CONH₂,         oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl,         (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl,         thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl,         isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,         (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl,         1-methylpyrazol-4-yl, isothiazol-4-yl,         1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl or         1-methyl-2-oxopyrrolidin-4-yl;     -   or R₁₁ and R₁₂ combine together with the N atom to which they         are attached to form a pyrrolidinyl,         2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl,         2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl,         piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,         4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,         4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,         4,4-difluoro-piperidinyl, N4-methyl-piperazinyl,         N4-(N,N-dimethyl)acetamide-piperazinyl,         N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,         1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,         2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl,         1,4-dioxa-8-azaspiro[4.5]decanyl group,         6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl,         3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl,         2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl,         3-fluoromethylpyrrolidinyl or         3-(N,N-dimethylacetamide)pyrrolidinyl;     -   R₁₃ is hydrogen or methyl; and     -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,         tetrahydropyran-4-yl or pyridin-3-yl.     -   R₆ is preferably —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one         —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;

-   -   wherein:     -   R₇ is methyl;     -   R₈ is hydrogen or methyl;     -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,         2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,         1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl,         cyclopentyl, tetrahydrofuran-3-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl or         pyridin-3-yl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a pyrrolidinyl, piperidinyl,         4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or         morpholinyl group;     -   R₁₀ is hydrogen, methyl or ethyl;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl,         (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,         (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl,         2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl,         2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,         2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,         3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl,         cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl,         2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl,         2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl,         4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt,         tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl,         tetrahydropyran-3-yl, tetrahydropyran-4-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl,         pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH) or CH(CH₃)CONH₂;     -   or R₁₁ and R₁₂ combine together with the N atom to which they         are attached to form a pyrrolidinyl,         2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl,         2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl,         piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,         4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,         4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,         4,4-difluoro-piperidinyl, N4-methyl-piperazinyl,         N4-(N,N-dimethyl)acetamide-piperazinyl,         N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,         1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,         2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl or         1,4-dioxa-8-azaspiro[4.5]decanyl group;     -   R₁₃ is hydrogen or methyl; and     -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,         tetrahydropyran-4-yl or pyridin-3-yl.

R₆ is preferably —(CH₂)_(m)—X wherein m is 1 or 2 and X is —NR₈R₉, or —CONR₁₁R₁₂;

-   -   wherein:     -   R₈ is hydrogen or methyl;     -   R₉ is 5- or 6-membered heterocyclyl optionally substituted with         one or two oxo substituents;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a 5- or 6-membered N-heterocyclyl group         optionally substituted with one substituent selected from         methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl,         methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or         with one or two substituents selected from fluoro and oxo;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is 4-, 5- or 6-membered heterocyclyl optionally substituted         with one or two substituents selected from oxo and methyl;     -   or R₁₁ and R₁₂ combine together with the N atom to which they         are attached to form a 5- or 6-membered N-heterocyclyl group         optionally substituted with one substituent selected from         monofluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl,         methoxymethyl, methylsulfonyl, cyano, amido,         (N,N-dimethyl)acetamide and pyridyl, or with one or two         substituents selected from fluoro, methyl and oxo.     -   R₆ is most preferably —(CH₂)_(m)—X wherein m is 2 or 3 and X is         —NR₈R₉;     -   wherein:     -   R₈ is hydrogen; and     -   R₉ is 5- or 6-membered heterocyclyl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a 5- or 6-membered N-heterocyclyl group.

B5. Substituent A

A is selected from the group consisting of C₅-C₇ cycloalkyl, furanyl, thiophenyl, methylthiophenyl and

wherein:

-   -   X₁ is hydrogen, halo or methyl;     -   X₁′ is hydrogen or halo;     -   X₂ is hydrogen, halo or methyl;     -   X₂′ is hydrogen or halo; and     -   X₃ is hydrogen or fluoro.

Preferably A is

wherein X₁, X₁′, X₂, X₂′ and X₃ are as defined above.

More preferably A is

wherein:

-   -   X₁ is hydrogen, fluoro or chloro;     -   X₁′ is hydrogen, fluoro or chloro;     -   X₂ is hydrogen, fluoro, chloro or bromo;     -   X₂′ is hydrogen, fluoro, chloro or bromo; and     -   X₃ is hydrogen or fluoro.

In one preferred embodiment not all of X₁, X₁′, X₂, X₂′ and X₃ are hydrogen. Preferably A is selected from the group consisting of

More preferably A is selected from the group consisting of

Even more preferably A is selected from the group consisting of

Most preferably A is selected from the group consisting of

B6. Specific Embodiments of Compounds of Formula I

Various embodiments of substituents R₁, R₄, R₅, R₆, A, X, X₁, X₁′, X₂, X₂′ and X₃ have been discussed in B1 to B5 above. These “substituent” embodiments can be combined with any of the “core structure” embodiments, discussed in B0 above, to form further embodiments of compounds of formula Ia. All embodiments of compounds of formula Ia formed by combining the “substituent” embodiments and “core structure” embodiments, discussed above, are within the scope of Applicants' invention, and some preferred further embodiments of the compounds of formula Ia are provided below.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

-   -   R₁ is selected from the group consisting of hydrogen, C₁-C₆         alkyl and partially or fully deuterated C₁-C₆ alkyl;     -   R₄ (if present) is selected from the group consisting of         hydrogen and methyl;     -   R₅ (if present) is hydrogen;     -   R₆ is selected from the group consisting of —COOH, —CHO, or         —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within         —(CH₂)_(m)— may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;

wherein:

-   -   R₇ is methyl;     -   R₈ is hydrogen or methyl;     -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,         2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,         1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl,         cyclopentyl, tetrahydrofuran-3-yl, (tetrahydrofuran-2-yl)methyl,         (1,1-dioxido)tetrahydrothiopyran-4-yl,         (tetrahydro-2H-pyran-4-yl)methyl, pyridin-2-yl, pyridin-3-yl,         tetrahydropyran-3-yl, cyclohexyl, (pyridine-2-yl)methyl or         (1-methylpyrazol-4-yl)methyl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a pyrrolidinyl, piperidinyl,         4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or         morpholinyl group;     -   R₁₀ is hydrogen, methyl or ethyl;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl,         (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,         (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl,         2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl,         2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,         2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,         3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl,         cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl,         2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl,         2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl,         4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt,         tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl,         tetrahydropyran-3-yl, tetrahydropyran-4-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl,         pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH), CH(CH₃)CONH₂,         oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl,         (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl,         thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl,         isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,         (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl,         1-methylpyrazol-4-yl, isothiazol-4-yl,         1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl,         1-methyl-5-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl;     -   or R₁₁ and R₁₂ combine together with the N atom to which they         are attached to form a pyrrolidinyl,         2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl,         2-trifluoromethyl-pyrrolidinyl, 3-(fluoromethyl)pyrrolidinyl,         3-methylsulfonyl-pyrrolidinyl,         N,N-dimethylpyrrolidinyl-3-carboxamide, isoxazolidin-2-yl,         piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,         4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,         4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,         4,4-difluoro-piperidinyl, N,N-dimethylpiperidinyl-4-carboxamide,         N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl,         N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,         1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,         2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl,         1,4-dioxa-8-azaspiro[4.5]decanyl group,         6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl,         3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl,         2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl,         3-fluoromethylpyrrolidinyl or         3-(N,N-dimethylacetamide)pyrrolidinyl;     -   R₁₃ is hydrogen or methyl; and     -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,         tetrahydropyran-4-yl or pyridin-3-yl; and

A is

wherein:

-   -   X₁ is hydrogen, halo or methyl;     -   X₁′ is hydrogen or halo;     -   X₂ is hydrogen, halo or methyl;     -   X₂′ is hydrogen or halo; and     -   X₃ is hydrogen or fluoro.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

-   -   R₁ is selected from the group consisting of hydrogen, C₁-C₆         alkyl and partially or fully deuterated C₁-C₆ alkyl;     -   R₄ (if present) is selected from the group consisting of         hydrogen and methyl;     -   R₅ (if present) is hydrogen;     -   R₆ is selected from the group consisting of —COOH, —CHO, or         —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within         —(CH₂)_(m)— may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;

wherein:

-   -   R₇ is methyl;     -   R₈ is hydrogen or methyl;     -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,         2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,         1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl,         cyclopentyl, tetrahydrofuran-3-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl,         pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl,         (pyridine-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R₈ and         R₉ combine together with the N atom to which they are attached         to form a pyrrolidinyl, piperidinyl,         4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or         morpholinyl group;     -   R₁₀ is hydrogen, methyl or ethyl;     -   R₁₁ is hydrogen or methyl;     -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl,         (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,         (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl,         2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl,         2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,         2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,         3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl,         cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl,         2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl,         2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl,         4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt,         tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl,         tetrahydropyran-3-yl, tetrahydropyran-4-yl,         (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl,         pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH), CH(CH₃)CONH₂,         oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl,         (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl,         thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl,         isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,         (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl,         1-methylpyrazol-4-yl, isothiazol-4-yl,         1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl or         1-methyl-2-oxopyrrolidin-4-yl;     -   or R₁ and R₁₂ combine together with the N atom to which they are         attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl,         2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl,         3-methylsulfonyl-pyrrolidinyl, piperidinyl,         3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,         4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,         4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,         4,4-difluoro-piperidinyl, N4-methyl-piperazinyl,         N4-(N,N-dimethyl)acetamide-piperazinyl,         N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,         1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,         2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl,         1,4-dioxa-8-azaspiro[4.5]decanyl group,         6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl,         3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl,         2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl,         3-fluoromethylpyrrolidinyl or         3-(N,N-dimethylacetamide)pyrrolidinyl;     -   R₁₃ is hydrogen or methyl; and     -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,         tetrahydropyran-4-yl or pyridin-3-yl; and

A is

wherein:

-   -   X₁ is hydrogen, halo or methyl;     -   X₁′ is hydrogen or halo;     -   X₂ is hydrogen, halo or methyl;     -   X₂′ is hydrogen or halo; and     -   X₃ is hydrogen or fluoro.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

-   -   R₁ is selected from the group consisting of hydrogen, C₁-C₆         alkyl and partially or fully deuterated C₁-C₆ alkyl.     -   R₄ (if present) is selected from the group consisting of         hydrogen and methyl.     -   R₅ (if present) is hydrogen.     -   R₆ is selected from the group consisting of —COOH, —CHO, or         —(CH₂)_(m)—X wherein m is 1, 2 or 3 and one —CH₂— moiety within         —(CH₂)_(m)— may optionally be replaced by

-   -    and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂),         —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl,         3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl,         pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀,         —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄;         -   wherein:         -   R₇ is methyl;         -   R₈ is hydrogen or methyl;         -   R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl,             2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,             1-cyclohexylethyl, isopropyl, butyl, cyclopropyl,             cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl,             (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl or             pyridin-3-yl;         -   or R₈ and R₉ combine together with the N atom to which they             are attached to form a pyrrolidinyl, piperidinyl,             4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or             morpholinyl group;         -   R₁₀ is hydrogen, methyl or ethyl;         -   R₁₁ is hydrogen or methyl;         -   R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl,             benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl,             (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl,             2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl,             1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl,             2-(1H-pyrazol-1-yl)ethyl,             2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl,             3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl,             butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl,             cyclopentyl, 2-hydroxycyclopentyl,             2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl,             2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano,             methylsulfonyl, CH₂COOEt, tetrahydrofuran-3-yl,             2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl,             tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl,             1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl,             CH₂CH(NH₂)(COOH) or CH(CH₃)CONH₂;         -   or R₁₁ and R₁₂ combine together with the N atom to which             they are attached to form a pyrrolidinyl,             2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl,             2-trifluoromethyl-pyrrolidinyl,             3-methylsulfonyl-pyrrolidinyl, piperidinyl,             3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl,             4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl,             4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl,             4,4-difluoro-piperidinyl, N4-methyl-piperazinyl,             N4-(N,N-dimethyl)acetamide-piperazinyl,             N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl,             1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl,             2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl             or 1,4-dioxa-8-azaspiro[4.5]decanyl group;         -   R₁₃ is hydrogen or methyl; and         -   R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl,             tetrahydropyran-4-yl or pyridin-3-yl

A is

wherein:

-   -   X₁ is hydrogen, halo or methyl;     -   X₁′ is hydrogen or halo;     -   X₂ is hydrogen, halo or methyl;     -   X₂′ is hydrogen or halo; and     -   X₃ is hydrogen or fluoro.

In other embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

-   -   R₁ is selected from the group consisting of hydrogen and methyl;     -   R₄ (if present) is hydrogen;     -   R₅ (if present) is hydrogen;     -   R₆ is —(CH₂)_(m)—X wherein m is 1 or 2 and X is —NR₈R₉, or         —CONR₁₁R₁₂;         -   wherein:         -   R₈ is hydrogen or methyl;         -   R₉ is 5- or 6-membered heterocyclyl optionally substituted             with one or two oxo substituents;         -   or R₈ and R₉ combine together with the N atom to which they             are attached to form a 5- or 6-membered N-heterocyclyl group             optionally substituted with one substituent selected from             methyl, trifluoromethyl, hydroxy, hydroxymethyl,             methoxymethyl, methylsulfonyl, amido,             (N,N-dimethyl)acetamide and pyridyl or with one or two             substituents selected from fluoro and oxo;         -   R₁₁ is hydrogen or methyl;         -   R₁₂ is 4-, 5- or 6-membered heterocyclyl optionally             substituted with one or two substituents selected from oxo             and methyl;         -   or R₁₁ and R₁₂ combine together with the N atom to which             they are attached to form a 5- or 6-membered N-heterocyclyl             group optionally substituted with one substituent selected             from monofluoromethyl, trifluoromethyl, hydroxy,             hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido,             (N,N-dimethyl)acetamide and pyridyl, or with one or two             substituents selected from fluoro, methyl and oxo; and     -   A is selected from the group consisting of

In other embodiments of formula Ia structures of formula If are highly preferred

wherein:

-   -   R₁ is selected from the group consisting of hydrogen and methyl;     -   R₄ is hydrogen;     -   R₅ is hydrogen;     -   R₆ is —(CH₂)_(m)—X wherein m is 2 or 3 and X is —NR₈R₉;     -   wherein:     -   R₈ is hydrogen; and     -   R₉ is 5- or 6-membered heterocyclyl;     -   or R₈ and R₉ combine together with the N atom to which they are         attached to form a 5- or 6-membered N-heterocyclyl group; and

A is selected from the group consisting of

Especially preferred embodiments of compounds of formula Ia are described in Examples 1 to 478 below. Where these examples describe the preparation of a compound of formula Ia in the form of a pharmaceutically acceptable salt or solvate, it will be appreciated that the present invention also relates to said compound in the form of the corresponding free acid or free base. Similarly, where these examples describe the preparation of a compound of formula Ia in the form of a free acid or free base, it will be appreciated that the present invention also relates to said compound in the form of a pharmaceutically acceptable salt or solvate thereof.

The non-salt, non-solvated forms of of Examples 1 to 478 are listed below. The invention also relates to the pharmaceutically acceptable salts or solvates of each of these individual compounds. Should any of these compounds exist as tautomers, each tautomeric form, and mixtures thereof, are contemplated as included in the present invention.

-   Example 1: (S)-ethyl     2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 2: (S)-ethyl     2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 3:     (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 4: Methyl     2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 5: methyl     2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 6:     2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 7:     2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid. -   Example 8:     (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 9:     (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone -   Example 10:     (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 11:     (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 12:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 13:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 14:     (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 15:     (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 16:     (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 17:     (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 18:     (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 19:     (S)-N-cyano-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 20:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide -   Example 21:     (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide -   Example 22:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxotetrahydrofuran-3-yl)acetamide -   Example 23:     (R)-N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 24:     (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide -   Example 25: ethyl     (R)-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)glycinate -   Example 26:     (S)-2-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanamide -   Example 27:     (R)-N-(cyanomethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 28:     N-((1r,4R)-4-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 29:     N-(2-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 30:     (R)-N,N-dimethyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 31:     (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic     acid -   Example 32:     ((R)-N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 33:     2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 34:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxocyclopentyl)acetamide -   Example 35:     (5aS,6aR)-1-(2-aminoethyl)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 36:     2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile -   Example 37:     N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide -   Example 38:     N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide -   Example 39:     (5aS,6aR)-1-(2-(butyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 40:     (5aS,6aR)-1-(2-(benzyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 41:     (5aS,6aR)-1-((1H-tetrazol-5-yl)methyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 42:     (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 43:     (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic     acid -   Example 44: ethyl     2-(5a-(thiophen-2-yl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 45:     (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde -   Example 46:     (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 47:     (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 48:     (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 49:     (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(3-phenylpropyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 50:     (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 51:     2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 52:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 53:     2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 54: ethyl     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 55: ethyl     2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 56:     (2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 57:     2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 58:     2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 59: ethyl     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 60: ethyl     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 61: ethyl     (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 62: ethyl     (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 63: ethyl     (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 64: ethyl     (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 65: ethyl     (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate -   Example 66:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 67:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 68:     2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide -   Example 69:     2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N,N-dimethylacetamide -   Example 70:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one -   Example 71:     (R)-N-(3-(dimethylamino)propyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 72:     (R)-N-(2-hydroxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 73:     (R)-N-(2-methoxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 74:     (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 75:     2-((R)-6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 76:     (R)-N-cyclopentyl-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 77:     2-((R)-6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 78 (:     (R)-N-cyclopropyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 79:     (R)-N-(cyclopropylmethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 80:     (R)-N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 81:     (R)-1-(4-methylpiperazin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 82:     (R)-1-(4-hydroxypiperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 83:     (R)-1-(4-(hydroxymethyl)piperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 84:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 85:     (R)-N,N-dimethyl-2-(4-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-1-yl)acetamide -   Example 86:     (R)-1-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperidine-4-carboxamide -   Example 87:     (R)-1-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 88:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 89:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(3-morpholinopropyl)acetamide -   Example 90:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 91:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one -   Example 92:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-butyl-N-methylacetamide -   Example 93:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide -   Example 94:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide -   Example 95:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide -   Example 96:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 97:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-propylacetamide -   Example 98:     1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 99:     (S)-N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 100:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one -   Example 101:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one -   Example 102:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide -   Example 103:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide -   Example 104:     (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 105:     (S)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 106:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide -   Example 107:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide -   Example 108:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 109:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide -   Example 110:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one -   Example 111:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one -   Example 112:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide -   Example 113:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 114:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide -   Example 115:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)acetamide -   Example 116:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 117:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one -   Example 118:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide -   Example 119:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide -   Example 120:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(hydroxymethyl)cyclopentyl)acetamide -   Example 121:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-hydroxypiperidin-1-yl)ethan-1-one -   Example 122: tert-butyl     (R)-2-((2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)methyl)pyrrolidine-1-carboxylate -   Example 123:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one -   Example 124:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide -   Example 125:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one -   Example 126:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one -   Example 127:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-1-cyclohexylethyl)acetamide -   Example 128:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 129:     (R)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 130:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide -   Example 131:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide -   Example 132:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexyl-N-methylacetamide -   Example 133:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 134:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)acetamide -   Example 135:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one -   Example 136:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one -   Example 137:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-thiomorpholinoethan-1-one -   Example 138:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-7-azaspiro[4.4]nonan-7-yl)ethan-1-one -   Example 139:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide -   Example 140:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 141:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 142:     N-(2-(1H-pyrazol-1-yl)ethyl)-2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 143:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide -   Example 144:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide -   Example 145:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide -   Example 146:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(3-(dimethylamino)propyl)acetamide -   Example 147:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethan-1-one -   Example 148:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide -   Example 149:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one -   Example 150:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 151:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide -   Example 152:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 153:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide -   Example 154:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide -   Example 155:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide -   Example 156:     N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 157:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 158:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one -   Example 159:     (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide -   Example 160:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)acetamide -   Example 161:     2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)acetamide -   Example 162:     (S)-N-(2-(1H-pyrazol-1-yl)ethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 163:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide -   Example 164:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one -   Example 165:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-8-azaspiro[4.5]decan-8-yl)ethan-1-one -   Example 166:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1-oxidothiomorpholino)ethan-1-one -   Example 167:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 168:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide -   Example 169:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide -   Example 170:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide -   Example 171:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide -   Example 172:     (R)-1-(2-hydroxyethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 173:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 174:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 175:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(isopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 176:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 177:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 178:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 179:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 180:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 181:     (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(cyclobutylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 182:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 183:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 184:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-1-cyclohexylethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 185:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 186:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((cyclopropylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 187:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 188:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclobutylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 189:     (5aS,6aR)-1-(2-(benzylamino)ethyl)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 190:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentyl(methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 191:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 192:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyridin-2-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 193:     (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 194:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 195:     (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 196:     (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 197:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(pyridin-3-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 198:     (R)-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 199:     (R)-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 200: (R)-diethyl     2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate     Example 201:     (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic     acid -   Example 202:     (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic     acid -   Example 203:     (R)-N-(cyclopropylmethyl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide -   Example 204:     (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 205:     (R)-1-morpholino-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 206:     (R)-1-(4,4-difluoropiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 207:     (R)-1-(piperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 208:     (R)-1-(4-methylpiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 209:     (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 210:     (R)-1-(pyrrolidin-1-ylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 211:     (R)-1-(((2-hydroxyethyl)(methyl)amino)methyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 212:     (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 213:     (R)-1-(2-(pyridin-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 214:     (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 215:     (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 216:     (R)-1-(3-ethoxypropyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 217:     (R)-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 218:     (R)-1-(2-(pyridin-4-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 219:     (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 220:     (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide -   Example 221:     (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide -   Example 222:     (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)tetrahydro-2H-pyran-4-carboxamide -   Example 223:     (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)nicotinamide -   Example 224:     2-{[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl]methyl}-1-cyanoguanidine     Example 225:     (S,Z)-N-((6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)-N′-cyanopyrrolidine-1-carboximidamide -   Example 226:     (S)-N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylnicotinamide -   Example 227:     (S)-N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide -   Example 228:     (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 229:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 230:     (S)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 231:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 232:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 233:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 234:     1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)cyclopropane-1-carboxamide -   Example 235:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one -   Example 236:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 237:     (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 238:     (S)-1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)cyclopropane-1-carboxamide -   Example 239:     (R)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 240:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 241:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one -   Example 242:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 243:     2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 244:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 245:     (R)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 246:     2-((R)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 247:     1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 248:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one -   Example 249:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 250:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 251:     2-((S)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 252:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 253:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide -   Example 254:     (R)-N-(1-cyanocyclopropyl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 255:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 256:     (S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 257:     (R)-2-methyl-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 258:     (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic     acid -   Example 259:     (R)-2-methyl-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione -   Example 260:     (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic     acid -   Example 261:     (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one -   Example 262:     (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide -   Example 263:     (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide -   Example 264:     (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one -   Example 265:     3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)propanamide -   Example 266:     (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one -   Example 267:     1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 268:     (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide -   Example 269:     (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide -   Example 270:     (R)-N-(cyanomethyl)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide -   Example 271:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 272:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 273:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide -   Example 274:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 275:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 276:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 277:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 278:     2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 279:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 280:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 281:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 282:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 283:     1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 284:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 285:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide -   Example 286:     (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide -   Example 287:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-4-yl)acetamide -   Example 288:     3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)propanamide -   Example 289:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 290:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide -   Example 291:     (S)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 292:     1-((R)-3-fluoropyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 293:     (R)-N-(2-hydroxyethyl)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 294:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide -   Example 295:     2-((R)-2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 296:     1-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 297:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 298:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 299:     (R)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 300:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 301:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 302:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide -   Example 303:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide -   Example 304:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide -   Example 305:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide -   Example 306:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 307:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 308:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 309:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one -   Example 310:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one -   Example 311:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one -   Example 312:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one -   Example 313:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 314:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 315:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide -   Example 316:     (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide -   Example 317:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide -   Example 318:     (R)-3-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one -   Example 319:     1-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one -   Example 320:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one -   Example 321:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one -   Example 322:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 323:     (R)-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one -   Example 324:     (R)-1-methyl-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one -   Example 325:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide -   Example 326:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one -   Example 327:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 328:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide -   Example 329:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 330:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 331:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydro-2H-pyran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 332:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide -   Example 333:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 334:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 335:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide -   Example 336:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide -   Example 337:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)acetamide -   Example 338:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide -   Example 339:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide -   Example 340:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide -   Example 341:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclohexylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 342:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-2-oxopyrrolidin-3-yl)acetamide -   Example 343:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-((pyridin-2-ylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 344:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one -   Example 345:     N-(2-cyanocyclopentyl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 346:     (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 347:     (R)-N-(isoxazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 348:     (S)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile -   Example 349:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)acetamide -   Example 350:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide -   Example 351:     (R)-N-(isothiazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 352:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide -   Example 353:     1-(3-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one -   Example 354:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-2-oxopiperidin-3-yl)acetamide -   Example 355:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide -   Example 356:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide -   Example 357:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide -   Example 358:     N,N-dimethyl-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carboxamide -   Example 359:     (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione -   Example 360:     2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 361:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 362:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 363:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 364:     N-methyl-N-(tetrahydrofuran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 365:     N-((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 366:     (R)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 367:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 368:     2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 369:     2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 370:     2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 371:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide -   Example 372:     (R)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 373:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 374:     N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide -   Example 375:     N-methyl-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide -   Example 376:     (R)-N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 377:     (R)-N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 378:     (R)-N-methyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 379:     (R)-N-methyl-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 380:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 381:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 382:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 383:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 384:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 385:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 386:     N-((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 387:     2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide -   Example 388:     N-(1-methyl-2-oxopyrrolidin-3-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 389:     2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide -   Example 390:     (R)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile -   Example 391:     2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)acetamide -   Example 392:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 393:     (R)-N-(oxetan-3-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 394:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 395:     2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide -   Example 396:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 397:     (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide -   Example 398:     (R)-N-methyl-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 399:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 400:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 401:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 402:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 403:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 404:     2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 405:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 406:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 407:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 408:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 409:     (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 410:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 411:     (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 412:     2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 413:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 414:     (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 415:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 416:     (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 417:     2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 418:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 419:     (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 420:     (R)-N-methyl-N-(oxetan-3-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide -   Example 421:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 422:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 423:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 424:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 425:     2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 426:     2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 427     (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide -   Example 428:     (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide -   Example 429:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 430:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide -   Example 431:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 432:     (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 433:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 434:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 435:     (S)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 436:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 437:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide -   Example 438:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 439:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 440:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 441:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 442:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide -   Example 443:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 444:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(isoxazolidin-2-yl)ethan-1-one -   Example 445:     (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 446:     2-((R)-6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 447     (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 448:     (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 449:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide -   Example 450:     (S)-1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile -   Example 451:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 452:     (S)-1-(2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpiperidine-4-carboxamide -   Example 453:     1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpyrrolidine-3-carboxamide -   Example 454:     (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide -   Example 455:     N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 456:     (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 457:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide -   Example 458:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(fluoromethyl)pyrrolidin-1-yl)ethan-1-one -   Example 459:     2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 460:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d₃)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one -   Example 461:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide -   Example 462:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic     acid -   Example 463:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 464:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide -   Example 465:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 466:     2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 467:     2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 468:     2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide -   Example 469:     (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d₃)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide -   Example 470:     R)-6-(2,3,6-trifluoropheny)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 471:     (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 472:     (R)-1-(3-(isopropylamino)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 473:     (R)-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 474:     (R)-2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 475:     (R)-1-(2-((((S)-tetrahydrofuran-2-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 476:     (R)-1-(2-(tert-butylamino)ethyl)-2-methyl-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 477:     (R)-2-methyl-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione -   Example 478:     (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

C. Compositions

The compounds of the invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. Accordingly, the present invention is also directed to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

D. Methods of Use

This invention is also directed to compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular for the treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to the use of compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a method for treating conditions ameliorated by inhibition of dopamine-beta-hydroxylase outside the CNS comprising administering a therapeutically effective amount of a compound of formula Ia, as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

Conditions ameliorated by inhibition of DβH outside the CNS can include, but are not limited to: cardiovascular disorders such as Angina, Hypertension, Chronic or Congestive Heart Failure, Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH).

Reference is made to the “Guidelines for the diagnosis and treatment of pulmonary hypertension” (European Heart Journal (2009) 30, 2493-2537) for details on the definition, classification and pathology and pathobiological features of PH.

Typically, pulmonary hypertension is a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death. It may be defined by a mean pulmonary artery pressure equal or greater than 25 mmHg at rest.

PH has been clinically classified by the WHO into 5 groups, according to the cause of the disease, and symptoms may differ, depending on the ‘group’ that caused the disease.

However, ‘common’ symptoms are as follows:

-   -   Difficulty in breathing or shortness of breath (main symptom)     -   Fatigue     -   Dizziness     -   Swelling in the ankles or legs (edema)     -   Bluish lips and skin (cyanosis)     -   Chest pain     -   Racing pulse and palpitations

A clinical classification of pulmonary hypertension (PH) has been undertaken and reported by McLaughlin et al in “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension”, J Am Coll Cardiol 53, 1573-1619, 2009. PH was classified as follows:

1. Pulmonary arterial hypertension (PAH)

-   -   1.1. Idiopathic (IPAH)     -   1.2. Familial (FPAH)     -   1.3. Associated with (APAH):         -   1.3.1. Connective tissue disorder         -   1.3.2. Congenital systemic-to-pulmonary shunts         -   1.3.3. Portal hypertension         -   1.3.4. HIV infection         -   1.3.5. Drugs and toxins         -   1.3.6. Other (thyroid disorders, glycogen storage disease,             Gaucher's disease, hereditary hemorrhagic telangiectasia,             hemoglobinopathies, chronic myeloproliferative disorders,             splenectomy)     -   1.4. Associated with significant venous or capillary involvement         -   1.4.1. Pulmonary veno-occlusive disease (PVOD)         -   1.4.2. Pulmonary capillary hemangiomatosis (PCH)     -   1.5. Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension with left heart disease

-   -   2.1. Left-sided atrial or ventricular heart disease     -   2.2. Left-sided valvular heart disease

3. Pulmonary hypertension associated with lung diseases and/or hypoxemia

-   -   3.1. Chronic obstructive pulmonary disease     -   3.2. Interstitial lung disease     -   3.3. Sleep disordered breathing     -   3.4. Alveolar hypoventilation disorders     -   3.5. Chronic exposure to high altitude     -   3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH)

-   -   4.1. Thromboembolic obstruction of proximal pulmonary arteries     -   4.2. Thromboembolic obstruction of distal pulmonary arteries     -   4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign         material)

5. Miscellaneous

Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

The WHO has also provided the following functional assessment classification:

Functional Symptomatic profile

Class

-   -   I Patients with pulmonary hypertension but without resulting         limitation of physical activity. Ordinary physical activity does         not cause dyspnoea or fatigue, chest pain, or near syncope     -   II Patients with pulmonary hypertension resulting in slight         limitation of physical activity. They are comfortable at rest.         Ordinary physical activity causes undue dyspnoea or fatigue,         chest pain, or near syncope     -   III Patients with pulmonary hypertension resulting in marked         limitation of physical activity. They are comfortable at rest.         Less than ordinary activity causes undue dyspnoea or fatigue,         chest pain, or near syncope     -   IV Patients with pulmonary hypertension with inability to carry         out any physical activity without symptoms. These patients         manifest signs of right heart failure. Dyspnoea and/or fatigue         may even be present at rest. Discomfort is increased by any         physical activity.

E. General synthetic methodology

The methods used for the synthesis of the compounds of the invention are illustrated by the schemes below. The starting materials and reagents used in preparing these compounds are available from commercial suppliers or can be prepared by methods obvious to those skilled in the art. To make the schemes easier to read, the option to incorporate deuterium at certain positions is not shown. Specifically, deuterated products can be produced using specifically deuterated starting materials, including, but not limited to, those used in Examples 1-478.

The starting material for compounds of formula If, when R₁═H can generally be synthesised by the method outlined in Scheme 1 as either enriched enantiomers or racemates:

The starting material for compounds of formula Ii, when R₁═H can generally be synthesised by the method outlined in Scheme 2 as either enriched enantiomers or racemates:

Compounds of formula If or Ii, with various identities for R₆, can generally be synthesised by the methods outlined in Schemes 3-15 as either enriched enantiomers or racemates:

Compounds wherein R₁ is C₁-C₆ alkyl, partially or fully deuterated C₁-C₆ alkyl or C₃-C₆ cycloalkyl can be synthesised using an alkyl isothiocyanate as shown in Scheme 16 below:

F. Examples

All compounds and intermediates were characterised by NMR. The spectra were recorded on a Bruker Avance III 600 MHz spectrometer with solvent used as internal standard. ¹³C spectra were recorded at 150 MHz and ¹H spectra were recorded at 600 MHz. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (br, broad; d, doublet; m, multiplet; s, singlet; t, triplet) and coupling constant (Hz).

Room temperature in the following protocols means the temperature ranging from 20° C. to 25° C.

Example 1: (S)-ethyl 2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate Step 1: (E)-1,3-difluoro-5-(2-nitrovinyl)benzene

To a solution of methanol (72 mL), water (36 mL), and 2.5 M sodium hydroxide (32.4 mL, 81 mmol) was added a solution of 3,5-difluorobenzaldehyde (10 g, 70.4 mmol) and nitromethane (4.36 mL, 81 mmol) in methanol (12.00 mL) dropwise over 30 min at 5° C., while the internal temperature was maintained between 5 and 10° C. with external cooling. The reaction was then agitated in the cold for an additional 0.5, and then a solution of cc. HCl (11.73 mL, 141 mmol) in water (36 mL) was added in one portion at 0-10° C. with stirring. The resulting crystals were collected, washed with water and dried to give the product as a light yellow powder. (Yield: 7.0 g, 54%).

Step 2: (S)-diethyl 2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate

To a stirred solution of (E)-1,3-difluoro-5-(2-nitrovinyl)benzene (7.4 g, 40.0 mmol) in dry tetrahydrofuran (75 mL) was added 4-((1R)-hydroxy((4S,8R)-8-vinylquinuclidin-2-yl)methyl)quinolin-6-ol (0.620 g, 1.999 mmol) at room temperature with stirring followed by addition of diethyl malonate (9.15 mL, 60.0 mmol). The mixture was cooled to −15 to −17° C. under inert atmosphere and stirred for 20 h in the cold. Thereupon, the mixture was evaporated to dryness under vacuum and the residue was taken up in dichloromethane (100 mL), washed with 1 M HCl, brine, dried over MgSO₄ and filtered on a silica pad. The filtrate was concentrated to 20 mL, and the residue was crystallized on dilution with petroleum ether (ca. 50 mL). The mixture was further diluted with petroleum ether (120 mL), and aged at 5-10° C. The resulting solid was collected, washed with petroleum ether, and dried to give the product as an off-white powder. (Yield: 11.46 g, 83%).

Step 3: (4S)-ethyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate

To a suspension of (S)-diethyl 2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate (11 g, 31.9 mmol) in methanol (170 mL) was added nickel(II) chloride hexahydrate (7.57 g, 31.9 mmol) followed by addition of sodium borohydride (9.64 g, 255 mmol) in portions with ice cooling. The mixture was stirred for 6 h at room temperature, then quenched with ammonium chloride solution (300 mL), diluted with dichloromethane (150 mL), acidified with 6 M HCl to pH=2, and stirred for 16 h. Thereupon, the mixture was extracted with dichloromethane, the organic phase was dried over MgSO₄ and evaporated to dryness to give the product as a light yellow crystalline. (Yield: 8.31 g, 97%).

Step 4: (4S)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid

To a stirred solution of (4S)-ethyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate (8.3 g, 30.8 mmol) in ethanol (130 mL) was added 1 M sodium hydroxide (37.0 mL, 37.0 mmol). The resulting suspension was stirred for 1 h, the organics were then removed under vacuum, and the residue was dissolved in water (300 mL). The product was crystallized on acidification with 6 M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50° C. to give the product as a beige powder Yield: 6.0 g, 81%.

Step 5: (S)-4-(3,5-difluorophenyl)pyrrolidin-2-one

A solution of (4S)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (6.0 g, 24.88 mmol) in toluene (350 mL) was stirred under reflux for 3 h, whereupon the mixture was evaporated to 30 mL, and then diluted with petroleum ether. The resulting crystals were collected, washed with petroleum ether and dried under vacuum to give an off-white powder. Yield: 4.83 g, 98%.

Step 6: (S)-tert-butyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate

To a stirred solution of (S)-4-(3,5-difluorophenyl)pyrrolidin-2-one (4.8 g, 24.34 mmol) in dry dichloromethane (15 mL) was added at room temperature di-tert-butyl dicarbonate (7.80 g, 36.5 mmol) followed by addition of N,N-dimethylpyridin-4-amine (2.97 g, 24.34 mmol) and triethyl amine (3.32 ml, 23.84 mmol). The mixture was then stirred at room temperature for 3 h, and then concentrated under vacuum. Chromatography (petroleum-ether-ethyl acetate; 4:1) gave an oil which was crystallized from petroleum ether (60 mL). The product was isolated as a white powder. Yield: 6.24 g, 88%.

Step 7: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate

To a stirred solution of (S)-tert-butyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate (2.5 g, 8.41 mmol) in dry diethyl ether (37 mL) was added dropwise 65% RED-Al (bis(2-methoxyethoxy)aluminum(III) sodium hydride) (1.51 ml, 5.05 mmol) in toluene at 0-5° C. under nitrogen and the mixture was stirred for 1 h in the cold. Thereupon, the mixture was quenched with sodium bicarbonate solution and stirred for 30 min. The organic phase was dried over MgSO₄, and evaporated to dryness to give the product as a yellowish oil. (Yield: 2.56 g, 92%).

Step 8: (4S)-tert-butyl 2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (3.5 g, 11.69 mmol) in dry dichloromethane (75 mL) was added trimethylsilanecarbonitrile (3.14 ml, 23.39 mmol) followed by addition of boron trifluoride etherate (3.26 ml, 25.7 mmol) at −70° C. The mixture was stirred for 4 h in the cold, thereupon quenched with sodium bicarbonate solution, and then allowed to warm up with stirring to room temperature. The organic phase was dried over MgSO₄, filtered and evaporated to dryness under vacuum. Chromatography (petroleum ether-ethyl acetate; 9:1) afforded the compound as a colourless oil. (Yield: 2.43 g, 67%).

Step 9: (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid

To a stirred solution of (4S)-tert-butyl 2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (2.25 g, 7.30 mmol) in ethanol (25 mL) was added 3 M sodium hydroxide (12.16 mL, 36.5 mmol) and the solution was gently refluxed (oil bath at 80° C.) for 3 h. Thereupon, ethanol was removed under vacuum and the residue was diluted with water (30 mL), and then acidified with 2 M HCl to pH=2 at 10-15° C. The mixture was extracted with dichloromethane (50 mL), the insoluble materials in both phases was filtered off, whereupon the organic phase was washed with brine, dried over MgSO₄ and evaporated to dryness to give 0.90 g of yellowish foam. (Yield: 37%).

Step 10: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)pyrrolidine-1-carboxylate

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (0.35 g, 1.069 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.154 g, 1.069 mmol) and N,N-dimethylpyridin-4-amine (0.131 g, 1.069 mmol) was added dicyclohexylmethanediimine (0.221 g, 1.069 mmol) dropwise at 0-5° C. and the mixture was stirred in the cold for 2 h. The mixture was then filtered through a celite, plug, the filtrate was washed with 1 M HCl, brine, dried over MgSO₄, and then evaporated to dryness to give the product as oil. (Yield: 0.42 g, 87%).

Step 11: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate

A solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)pyrrolidine-1-carboxylate (0.41 g, 0.904 mmol) in abs. ethanol (5 mL) was stirred under reflux for 3 h. The solvent was then removed under vacuum and the residue was subjected to chromatography (petroleum ether-ethyl acetate; 9:1). The product was isolated as a colourless oil. (Yield: 0.124 g, 34%).

Step 12: ((S)-ethyl 2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate

A solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (0.11 g, 0.277 mmol) in 2 M HCl (1.107 mL, 2.214 mmol) in diethyl ether was stirred at room temperature for 5 h. and then the solvent was removed under vacuum. The residue was dissolved in a mixture of ethanol (1.5 mL) and water (1.5 mL), treated with potassium thiocyanate (0.030 g, 0.304 mmol) followed by addition of 6N HCl (0.023 mL, 0.138 mmol) and then the mixture was stirred at 90° C. for 3 h. Thereupon, ethanol was removed under vacuum, and the residue was extracted with a mixture of ethyl acetate-petroleum ether (2:1). The organic phase was dried over MgSO₄, evaporated to dryness and the residue was subjected to chromatography (petroleum ether-EtOAc; 1:1, then 1:2). The product was isolated as a light yellow powder. (Yield: 0.038 g, 40%).

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 7.13 (3H, m), 4.17 (1H, dd, J=11.1, 7.8 Hz), 4.09 (2H, q, J=7.0 Hz), 4.09 (1H, m), 3.70 (1H, dd, J=11.2, 7.8 Hz), 3.52 (2H, m, J=3.1 Hz), 3.20 (1H, dd, J=15.4, 7.9 Hz), 2.84 (1H, dd, J=15.4, 8.4 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 163.3, 163.2, 161.7, 161.6, 155.6, 145.8, 145.8, 145.7, 129.9, 113, 110.7, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 60.7, 50.3, 46.4, 30.4, 29.8, 14.1.

Example 2: (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate and Example 3: (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Step 1: tert-butyl (4S)-4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate

A mixture of potassium 3-ethoxy-3-oxopropanoate (0.741 g, 4.35 mmol) and magnesium bromide diethyletherate (0.749 g, 2.90 mmol) in dry tetrahydrofuran (10 ml) was stirred under inert atmosphere at 50° C. for 6 h. In parallel, di(1H-imidazol-1-yl)methanone (0.706 g, 4.35 mmol) was added portionwise to a solution of (4S)-1-(tert-butoxycarbonyl)-4-(2,5-difluorophenyl)pyrrolidine-2-carboxylic acid (prepared analogous manner to Example 1 step 9) (0.95 g, 2.90 mmol) in dry tetrahydrofuran (8.00 mL) at 0-5° C. and the mixture was stirred for 2 h at room temperature. The solution was then added to the first suspension dropwise and the mixture was stirred for 16 h at ambient temperature. Thereupon, the mixture was quenched with aq. NaHSO₄ solution and then extracted with a mixture of ethyl acetate-petroleum ether (2:1). The organic phase was washed with sodium bicarbonate, dried over MgSO₄ and evaporated to dryness. Chromatography in a mixture of petroleumether-ethyl acetate (9:1) afforded (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate. (Yield: 0.56 g, 48.6%).

Step 2: (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate and (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

A solution of (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (0.56 g, 1.409 mmol) in 2 M HCl (5.64 mL, 11.27 mmol) in diethyl ether was stirred at room temperature for 16 h, whereupon the solvent was removed under vacuum, and the residue was dissolved in a mixture of ethanol (6 mL) and water (6 mL). The reaction mixture was treated with potassium thiocyanate (0.151 g, 1.550 mmol) followed by addition of 6 M HCl (0.117 mL, 0.705 mmol) and then stirred for 2 h Thereupon, ethanol was removed under vacuum, were upon the resulting solid was collected and washed with water. The precipitate was dissolved in ethyl acetate, dried over MgSO₄, filtered through a silica pad, and then evaporated to dryness. Crystallization from petroleum ether afforded (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate as an off-white powder. (Yield: 0.19 g, 39%).

¹H NMR (DMSO_(d6)): 11.79 (1H, br s), 7.27 (2H, m), 7.18 (1H, m), 4.23 (1H, quin, J=7.7 Hz), 4.15 (1H, dd, J=11.2, 8.0 Hz), 4.09 (2H, q, J=7.1 Hz), 3.75 (1H, dd, J=11.2, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.5, 8.0 Hz), 2.87 (1H, br dd, J=15.6, 7.8 Hz), 1.19 (3H, t, J=7.0 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 159, 157.5, 157.1, 155.6, 155.5, 130.1, 130, 130, 129.9, 129.8, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.2, 115.1, 115, 113, 60.7, 49.4, 40.3, 29.8, 29.6, 14.1.

The aqueous mother liqueur of the above procedure was extracted with dichloromethane. The organic phase was extracted with aq. NaOH, then the aqueous phase was acidified and extracted with dichloromethane, The organic phase was dried over MgSO₄, evaporated to dryness to give 67 mg (15% yield) of (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid as an off-white powder.

¹H NMR (DMSO_(d6)): 12.58 (1H, br s), 11.75 (1H, s), 7.28 (2H, m), 7.18 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 7.9 Hz), 3.73 (1H, dd, J=11.3, 7.3 Hz), 3.43 (2H, m), 3.21 (1H, dd, J=15.5, 8.0 Hz), 2.87 (1H, dd, J=15.4, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 159.1, 157.5, 157.1, 155.5, 155.5, 130.1, 130, 130, 129.9, 129.5, 117.1, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.1, 115.1, 113.8, 49.4, 40.3, 30, 29.5.

Example 4: Methyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Step 1: ((1R,2S)-2-(aminomethyl)-2-(2,5-difluorophenyl)cyclopropyl)methanol

To a stirred solution of 2-(2,5-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) in dry terahydrofuran (100 mL), was added (R)-2-(chloromethyl)oxirane (6.13 mL, 78.0 mmol) at room temperature, under nitrogen. The reaction was then cooled to 15° C. and 2 M sodium bis(trimethylsilyl)amide in terahydrofuran (57.1 mL, 114.0 mmol) was added, dropwise at 15° C. over a period of 2 h. Thereupon, the thus obtained red mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction was diluted with dry terahydrofuran (100 mL), cooled to 0° C., and then sodium borohydride (9.88 g, 261 mmol) was added followed by dropwise addition of boron trifluoride etherate (33.10 ml, 261 mmol). The mixture was allowed to warm up to room temperature and stirred overnight. The resulting pale yellow suspension was cooled to 0° C. and carefully quenched with 2 M HCl (196 mL, 392 mmol). The terahydrofuran was then evaporated off and the aqueous phase was washed with diethyl ether.

The pH of the aqueous phase was set to pH=10 by adding 3 M sodium hydroxide and then extracted with dichloromethane. The organic phase was dried over MgSO₄, filtered and evaporated to dryness under vacuum to leave a yellow oil. (Yield: 12.91 g, 74%).

Step 2: tert-butyl (((1S,2R)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carbamate

To an ice-cold solution of ((1R,2S)-2-(aminomethyl)-2-(2,5-difluorophenyl)cyclopropyl)methanol (12.91 g, 60.5 mmol) in ethanol (207 mL) was added di-tert-butyl dicarbonate (13.21 g, 60.5 mmol). The solution was stirred at room temperature for 3 h and then the solvent was evaporated off under vacuum. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate). The product was isolated as a white powder. (Yield: 14.28 g, 64%).

Step 3: tert-butyl (1S,5R)-1-(2,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of oxalyl dichloride (4.39 mL, 50.10 mmol) in dry dichloromethane (120 mL), was added dropwise a solution of dimethylsulfoxide (4.12 mL, 100.0 mmol) in dry dichloromethane (22 mL) at −78° C. The reaction mixture was stirred in the cold for 15 min, and then a solution of tert-butyl tert-butyl (((1S,2R)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carbamate (14.28 g, 45.60 mmol) in dry dichloromethane (44 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h and then triethylamine (31.8 mL, 228.0 mmol) was added. The reaction was allowed to warm up gradually to room temperature and stirred at room temperature for 2 h. Thereupon, the mixture was washed three times with water, dried over MgSO₄, filtered and evaporated to dryness to give a yellow oil. (Yield: 14.5 g, ˜100%).

Step 4: tert-butyl (1S,5R)-4-cyano-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of tert-butyl (1S,5R)-1-(2,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (14.2 g, 45.60 mmol) in dry dichloromethane (230 mL) was added trimethylsilanecarbonitrile (16.33 ml, 122.0 mmol) at room temperature under nitrogen. The solution was then cooled to −78° C. and boron trifluoride etherate (16.83 mL, 134.0 mmol) was added dropwise. The reaction mixture was stirred in the cold for 4 h., and then saturated solution of sodium bicarbonate was added and allowed to warm up to room temperature. The organic phase was separated and aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO₄, filtered and evaporated to dryness to leave a yellow oil. (Yield: 14.9 g, 92%).

Step 5: (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

To a stirred solution of tert-butyl (1S,5R)-4-cyano-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (14.61 g, 45.6 mmol) in ethanol (145 mL), was added a solution of 3 M sodium hydroxide (76 mL, 228.0 mmol) at room temperature. The solution was heated at 80° C. for 4 h. and then was cooled to room temperature. Thereupon, ethanol was evaporated off and the aqueous phase was acidified with 2 M HCl solution and then extracted with a mixture of dichloromethane-isopropanol (7:3). The organic phase was dried over MgSO₄, filtered and evaporated to dryness to leave a yellow oil, which solidified on standing. (Yield: 17.0 g, 93%).

Step 6: (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.5 g, 7.37 mmol) in dichloromethane (50 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (1.062 g, 7.37 mmol) at room temperature followed by addition of N,N-dimethylpyridin-4-amine (0.900 g, 7.37 mmol). The thus obtained solution was cooled to 0° C. and a solution of N,N′-dicyclohexylcarbodiimide (1.520 g, 7.37 mmol) in dichloromethane was added dropwise. The mixture was stirred in the cold for 2 h, and then filtered through a celite plug. The filtrate was washed with 1 M HCl and brine, dried over MgSO₄, filtered and evaporated to dryness to give a yellow semisolid. Yield: 3.45 g, 100%.

Step 7: (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-methoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.43 g, 7.37 mmol) in dry methanol (40 mL), was heated at reflux for 3.5 h under inert atmosphere. The solution was then cooled to room temperature and the solvent was evaporated off. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 9/1, 4/1, 2/1, then 1/1). The product was isolated as a colourless oil. (Yield: 1.84 g, 53%).

Step 8: methyl 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanoate hydrochloride

(1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-methoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.79 g, 4.53 mmol) was stirred in 2 M ethereal HCl solution (18.11 mL, 36.2 mmol) for 8 h. Thereupon, the reaction mixture was evaporated to dryness to leave the product as a white foam. (Yield: 1.14 g, 76%).

Step 9: methyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

To a stirred solution of methyl 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanoate hydrochloride (1.14 g, 3.44 mmol) in a mixture of ethanol (14 mL) and water (14 mL) was added potassium thiocyanate (0.367 g, 3.78 mmol) followed by addition of cc. HCl (0.14 mL, 1.718 mmol). The solution was heated at reflux for 5 h, then cooled to room temperature and evaporated to dryness. The resulting oil was extracted from the aqueous phase with dichloromethane. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The thus obtained yellow oil was separated by chromatography (dichloromethane-methanol; 98:2, then 95:5), then chromatographed again (petroleum ether-ethyl acetate; 1:1, then 1:2). The product was isolated as a yellow solid. (Yield: 90 mg, 7%).

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.29 (1H, m), 7.26 (1H, m), 7.21 (1H, m), 4.10 (1H, br d, J=12.3 Hz), 3.82 (1H, d, J=12.0 Hz), 3.66 (3H, s), 3.59 (2H, m), 2.87 (1H, dd, J=8.2, 4.3 Hz), 1.67 (1H, dd, J=8.2, 5.4 Hz), 1.14 (1H, br t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 169.7, 158.8, 158.6, 157.2, 157, 156.3, 132.3, 128.6, 128.5, 128.4, 117.2, 117.1, 117, 117, 116.8, 116.8, 116, 115.9, 115.8, 115.7, 112.2, 52, 51.6, 51.5, 32.5, 29.6, 22.2, 20.7.

Example 5: methyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

(1R,5S)-3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was converted to methyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate by a similar procedure as described for Example 4 and the product was isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.11 (3H, m), 4.20 (1H, d, J=12.0 Hz), 4.06 (1H, d, J=12.2 Hz), 3.65 (3H, s), 3.57 (2H, m), 2.97 (1H, dd, J=8.2, 4.4 Hz), 1.70 (1H, dd, J=8.2, 5.3 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.7, 163.4, 163.3, 161.8, 161.7, 156.5, 144.8, 144.7, 144.7, 132.3, 112, 110, 110, 109.9, 109.8, 102.3, 102.1, 102, 52, 50.7, 36.2, 29.6, 25.2, 22.9.

Example 6: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

To a stirred solution of ethyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate (prepared analogous manner to Example 4) (275 mg, 0.785 mmol) in ethanol (3 mL) was added 1M sodium hydroxide (0.942 ml, 0.942 mmol) at room temperature and the solution was stirred for 2 h. Thereupon, a second crop of 1 M sodium hydroxide was added (0.942 ml, 0.942 mmol) and the reaction was allowed to stir for additional 1 h. Ethanol was then removed under vacuum and the aqueous phase was extracted dichloromethane. The aqueous phase was acidified to pH=1 by adding aqueous HCL solution and then extracted with dichloromethane. The organic phase was evaporated to dryness to give the product as a yellow foam. (Yield: 0.206 g, 76%).

¹H NMR (DMSO_(d6)): 12.57 (1H, br s), 11.70 (1H, s), 7.29 (1H, td, J=9.4, 4.6 Hz), 7.25 (1H, ddd, J=9.1, 5.9, 3.2 Hz), 7.21 (1H, m), 4.09 (1H, d, J=11.9 Hz), 3.81 (1H, d, J=12.0 Hz), 3.47 (2H, m), 2.87 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 158.8, 158.6, 157.2, 157, 157, 156.1, 132.1, 128.6, 128.6, 128.5, 128.5, 117.2, 117.1, 117, 117, 116.9, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 113, 51.6, 51.5, 32.5, 29.9, 22.3, 20.7.

Example 7: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared by a similar procedure as described for Example 6 and the product was isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 12.60 (1H, br s), 11.69 (1H, s), 7.10 (3H, m), 4.20 (1H, d, J=12.2 Hz), 4.05 (1H, d, J=12.2 Hz), 3.45 (2H, m), 2.98 (1H, dd, J=8.3, 4.3 Hz), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 163.4, 163.3, 161.8, 161.7, 156.3, 144.9, 144.8, 144.7, 132, 112.8, 110, 110, 109.8, 109.8, 102.3, 102.1, 101.9, 50.7, 36.2, 29.9, 25.3, 22.9.

Example 8: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of ethyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate (300 mg, 0.856 mmol) (analogous to Example 5) in a mixture of abs. methanol (2.3 mL) and dry tetrahydrofuran (2.3 mL) was added lithium chloride (0.061 ml, 3.00 mmol). The reaction mixture was then cooled to 0° C. and sodium borohydride (113 mg, 3.00 mmol) was added portionwise. The thus obtained white suspension was allowed to warm up to room temperature and stirred for 24 h. Thereupon, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄, filtered and evaporated to dryness to leave a yellow oil. Chromatography (petroleum ether-ethyl acetate; 1:1, 1:4, then 5% methanol in dichloromethane) followed by trituration with heptane afforded the product as a light yellow solid. (Yield: 0.065 g, 23%).

¹H NMR (DMSO_(d6)): 11.64 (1H, s), 7.10 (3H, m), 4.74 (1H, t, J=5.4 Hz), 4.17 (1H, d, J=12.0 Hz), 4.02 (1H, d, J=12.0 Hz), 3.59 (2H, m), 2.98 (1H, dd, J=8.2, 4.3 Hz), 2.53 (2H, td, J=6.8, 2.9 Hz), 1.65 (1H, dd, J=8.1, 5.2 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 163.4, 163.3, 161.8, 161.7, 155.9, 145.1, 145.1, 145, 130.9, 116.8, 109.9, 109.9, 109.8, 109.8, 102.2, 102, 101.9, 59.4, 50.5, 36, 28, 25.6, 22.9.

Example 9: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone Step 1: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate

A mixture of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (prepared according to protocol of Example 2 Step 1) (0.74 g, 1.862 mmol), morpholine (0.324 ml, 3.72 mmol) and N,N-dimethylpyridin-4-amine (0.068 g, 0.559 mmol) in toluene (3 mL) was stirred at 100° C. for 20 h. The reaction was then diluted with a mixture of ethyl acetate-petroleum ether (1:1) and washed with 1 M HCl. The organic phase was dried over MgSO₄, stripped down to dryness and purified by chromatography in a mixture of ethyl acetate-petroleum ether (1:1) to give (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate. Yield: 0.634 g, 78%.

Step 2: (1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-3-morpholinopropane-1,3-dione hydrochloride

A solution of (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate (0.66 g, 1.505 mmol) in 4 M HCl (7.53 mL, 30.1 mmol) in dioxane was stirred for 4 h at room temperature. Thereupon, the reaction mixture was diluted with diethyl ether, the resulting solid was collected, washed with diethyl ether and petroleumether, respectively and then dried in vacuum at 50° C. to give 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-3-morpholinopropane-1,3-dione hydrochloride as a white powder. Yield: 0.52 g, 92%.

Step 3: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

A solution of 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-3-morpholinopropane-1,3-dione hydrochloride (0.52 g, 1.387 mmol), potassium thiocyanate (0.148 g, 1.526 mmol) and 6 M HCl (0.12 ml, 0.69 mmol) in a mixture of ethanol (7 mL) and water (7.00 mL) was stirred under reflux for 1 h. Ethanol was evaporated under vacuum. The aqueous phase was extracted with ethyl acetate, the organic phase was diluted with petroleumether without drying until crystallization occurred. The resultant solid was collected and recrystallized from a mixture of DCM-petroleumether to give (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone as a white powder. (Yield: 0.051 g, 9%.)

¹H NMR (DMSO_(d6)): 11.66 (1H, s), 7.12 (3H, br d, J=8.2 Hz), 4.16 (1H, dd, J=11.1, 7.8 Hz), 4.07 (1H, quin, J=7.8 Hz), 3.69 (1H, dd, J=11.1, 7.8 Hz), 3.56 (4H, m), 3.52 (2H, s), 3.46 (4H, m), 3.15 (1H, br dd, J=15.2, 7.8 Hz), 2.80 (1H, br dd, J=15.3, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 163.3, 163.2, 161.7, 161.6, 155.4, 145.9, 145.8, 145.8, 129.4, 114.4, 110.7, 110.7, 110.6, 110.6, 102.6, 102.5, 102.3, 66, 50.2, 46.4, 45.7, 41.7, 30.5, 28.8.

Example 10: (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.58 (1H, m), 11.79 (1H, s), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.78 (1H, dd, J=11.7, 7.8 Hz), 3.41 (2H, s), 3.30 (1H, br dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.9, 8.0 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 155.3, 146.4, 145.3, 144.7, 143.7, 129.4, 120.5, 120.4, 120.3, 113.5, 105.9, 105.7, 105.6, 48.5, 35.7, 30, 29.1.

Example 11: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.58 (1H, br s), 11.74 (1H, br s), 7.13 (3H, m), 4.16 (1H, dd, J=11.2, 7.9 Hz), 4.08 (1H, quin, J=8.0 Hz), 3.70 (1H, dd, J=11.2, 7.8 Hz), 3.42 (2H, m), 3.20 (1H, dd, J=15.4, 7.8 Hz), 2.85 (1H, dd, J=15.4, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 163.3, 163.2, 161.7, 161.6, 155.5, 145.9, 145.8, 145.7, 129.7, 113.6, 110.8, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 50.3, 46.4, 30.4, 29.9.

Example 12: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(3-bromo-2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellowish solid.

¹H NMR (DMSO_(d6)): 12.56 (2H, m), 11.78 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.4 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.3 Hz), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.41 (2H, s), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.86 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.6, 118.8, 118.7, 118.5, 113.8, 113.8, 113.7, 113.6, 113.4, 104.1, 104.1, 103.9, 103.9, 48.7, 35.6, 29.9, 29.2.

Example 13: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(3-bromo-2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellowish solid.

¹H NMR (DMSO_(d6)): 12.56 (1H, br s), 11.78 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.6 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.4, 9.3 Hz), 3.73 (1H, dd, J=11.7, 8.0 Hz), 3.41 (2H, m), 3.26 (1H, dd, J=15.8, 9.4 Hz), 2.86 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.6, 118.8, 118.7, 118.5, 113.8, 113.8, 113.7, 113.6, 113.3, 104.1, 104.1, 103.9, 103.9, 48.7, 35.6, 29.9, 29.2.

Example 14: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale yellow solid.

¹H NMR (DMSO_(d6)): 12.60 (1H, s br), 11.78 (1H, s), 7.32-7.26 (2H, m), 7.18 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.3, 7.9 Hz), 3.73 (1H, dd, J=11.3, 7.5 Hz), 3.40 (2H, m), 3.21 (1H, dd, J=15.5, 8.0 Hz), 2.86 (1H, dd, J=15.5, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 159.1, 159.1, 157.5, 157.5, 157.1, 157.1, 155.5, 155.5, 155.5, 130.1, 130.1, 130, 130, 129.5, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.1, 115.1, 113.8, 49.4, 40.3, 30, 29.5.

Example 15: (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,3,5,6-tetrafluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 12.58 (1H, br s), 11.80 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.78 (1H, dd, J=11.7, 7.8 Hz), 3.41 (2H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 155.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.4, 120.5, 120.3, 120.2, 113.4, 105.9, 105.7, 105.6, 48.5, 35.7, 29.9, 29.1.

Example 16: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(5-bromo-2-fluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 12.58 (1H, br s), 11.76 (1H, br s), 7.59 (1H, dd, J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.8, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.3, 8.8 Hz), 4.22 (1H, quin, J=7.9 Hz), 4.14 (1H, dd, J=11.2, 8.1 Hz), 3.74 (1H, dd, J=11.2, 7.5 Hz), 3.43 (2H, m), 3.21 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.4, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 160.3, 158.7, 155.5, 131.9, 131.8, 131.4, 131.4, 130.7, 130.6, 129.5, 118, 117.9, 116.5, 116.5, 113.7, 49.3, 40.4, 29.9, 29.4.

Example 17: (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(5-chloro-2-fluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale yellow solid.

¹H NMR (DMSO_(d6)): 12.54 (1H, m), 11.75 (1H, s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=9.9, 8.9 Hz), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 8.0 Hz), 3.74 (1H, dd, J=11.3, 7.5 Hz), 3.42 (2H, m), 3.22 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.6, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 159.8, 158.2, 155.5, 130.3, 130.2, 129.5, 128.9, 128.9, 128.6, 128.5, 128.5, 128.5, 117.6, 117.4, 113.7, 49.3, 40.4, 29.9, 29.4.

Example 18: (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale pink solid.

¹H NMR (DMSO_(d6)): 12.55 (1H, br s), 11.76 (1H, s), 7.41 (1H, m), 7.13 (2H, m), 4.43 (1H, quin, J=8.8 Hz), 4.15 (1H, dd, J=10.6, 9.9 Hz), 3.72 (1H, dd, J=11.3, 8.4 Hz), 3.41 (2H, m), 3.24 (1H, dd, J=15.7, 9.2 Hz), 2.86 (1H, dd, J=15.7, 8.7 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 161.6, 161.6, 160, 159.9, 155.3, 129.8, 129.7, 129.7, 116.5, 116.4, 113.3, 112.3, 112.2, 112.1, 112.1, 48.7, 35.3, 29.9, 29.3.

Example 19: (S)-N-cyano-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred suspension of (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 10) (0.035 g, 0.1 mmol) in acetonitrile (1 ml) was added 1-hydroxypyrrolidine-2,5-dione (0.012 g, 0.100 mmol) followed by addition of N,N′-methanediylidenedicyclohexanamine (0.021 g, 0.100 mmol). The reaction was stirred at room temperature for 1 h. The mixture was diluted with N,N-dimethylformamide (1 mL), whereupon cyanamide (4.20 mg, 0.100 mmol) was added followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.017 ml, 0.100 mmol) and the mixture was stirred for 16 h at room temperature. Thereupon, the insoluble materials were filtered off, the filtrate was diluted with brine, acidified, and then extracted with dichloromethane. The organic phase was dried over MgSO₄ and then concentrated under reduced pressure. The product was crystallized on trituration with petroleum ether as a beige powder. (Yield: 0.015 g, 40%.) ¹H NMR (DMSO_(d6)): 11.94 (1H, br), 11.79 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.6 Hz), 4.19 (1H, dd, J=11.4, 9.4 Hz), 3.79 (1H, dd, J=11.7, 7.9 Hz), 3.56 (2H, br s), 3.30 (1H, br dd, J=16.0, 9.2 Hz), 2.92 (1H, dd, J=16.0, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 169.8, 155.8, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.8, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 130.4, 120.3, 120.2, 120.1, 111.7, 108.3, 105.9, 105.8, 105.6, 48.5, 35.8, 30.8, 29.1.

Example 20: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

To a stirred suspension of (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) (100 mg, 0.257 mmol)) in dry dichloromethane (3 mL) was added portionwise di(1H-imidazol-1-yl)methanone (45.8 mg, 0.283 mmol) at room temperature to give a clear solution. The mixture was stirred for 30 min, and then methanesulfonamide (26.9 mg, 0.283 mmol) was added followed by addition of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.039 mL, 0.257 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was poured onto 1 N HCl and extracted with ethyl acetate. The organic phase was washed with water and dried over MgSO₄. The solvent was concentrated in vacuum, and then purified by chromatography in a mixture of dichloromethane-methanol (9:1). Recrystallization from a mixture of diethyl ether-isopropanol afforded (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide as a brown solid. Yield: 30 mg, 22% a.

¹H NMR (DMSO_(d6)): 11.67 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.4 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.25 (2H, s), 3.25 (1H, dd, J=9.5, 15.6 Hz), 2.95 (3H, s), 2.86 (1H, dd, J=15.9, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 171, 160.9, 160.8, 159.2, 159.2, 157.6, 157.5, 155.9, 155.9, 154.8, 132.5, 132.4, 129.2, 118.8, 118.7, 118.5, 114.6, 113.8, 113.8, 113.7, 113.6, 104.1, 103.9, 48.5, 40.5, 35.7, 33.5, 29.5.

Example 21: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

Compound was prepared analogous manner to Example 20 from (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.90 (1H, br), 11.72 (1H, s), 7.60 (1H, dd, J=6.6, 2.2 Hz), 7.53 (1H, ddd, J=8.6, 4.4, 2.5 Hz), 7.23 (1H, dd, J=10.1, 9.0 Hz), 4.21 (1H, quin, J=7.9 Hz), 4.13 (1H, dd, J=11.1, 8.3 Hz), 3.73 (1H, dd, J=11.2, 7.7 Hz), 3.40 (2H, m), 3.21 (1H, br dd, J=15.4, 8.1 Hz), 3.12 (3H, s), 2.88 (1H, br dd, J=15.4, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 169.5, 160.3, 158.7, 155.4, 131.9, 131.8, 131.4, 131.4, 130.7, 130.6, 129.7, 118, 117.9, 116.5, 113.5, 49.2, 40.8, 40.4, 32.4, 29.6.

Example 22: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxotetrahydrofuran-3-yl)acetamide

A mixture of (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) (70 mg, 0.180 mmol), 3-aminodihydrofuran-2(3H)-one hydrobromide (32.7 mg, 0.180 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (34.5 mg, 0.180 mmol), N,N-dimethylpyridin-4-amine (24.17 mg, 0.198 mmol), N-ethyl-N-isopropylpropan-2-amine (0.041 mL, 0.234 mmol) in dry N,N dimethyl formamide (3 mL) was stirred for 3 h at room temperature. Thereupon, solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with saturated aq. NaHCO₃ solution and brine, respectively. The organic phase was dried over MgSO₄ and then evaporated. Chromatography in a mixture of dichloromethane methanol (9:1) afforded the titled product as a yellow solid. Yield: 50 mg, 53%.

¹H NMR (DMSO_(d6)): 11.80 (1H, s), 8.49 (1H, dd, J=7.8, 4.5 Hz), 7.73 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.6 Hz), 4.57 (1H, dtd, J=10.6, 8.7, 8.7, 2.4 Hz), 4.44 (1H, d quin, J=8.7, 3.9 Hz), 4.34 (1H, dt, J=1.3, 9.0 Hz), 4.20 (1H, ddd, J=10.5, 8.7, 6.6 Hz), 4.15 (1H, dd, J=9.5, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.31 (2H, t, J=5.9 Hz), 3.23 (1H, td, J=15.6, 9.4 Hz), 2.87 (1H, ddd, J=15.7, 10.7, 9.1 Hz), 2.39 (1H, m), 2.15 (1H, m).

¹³C NMR (DMSO_(d6)): 175.2, 167.8, 160.8, 160.8, 159.2, 159.2, 157.6, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.5, 129.5, 118.7, 118.6, 118.6, 118.5, 118.4, 118.4, 113.8, 113.8, 113.7, 113.6, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 65.3, 48.6, 48.5, 48.1, 35.7, 35.7, 31.2, 29.3, 28.2, 28.2.

Example 23: (R)-N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Step 1: (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

To a stirred suspension of (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 15) (1.8 g, 5.20 mmol) in dry dichloromethane (35 mL) was added di(1H-imidazol-1-yl)methanone (1.011 g, 6.24 mmol) portionwise at room temperature. The mixture was stirred for additional 30 min, the resulting solid was collected, washed with petroleum ether and dried on air to give (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone as a beige powder. Yield: 1.70 g, 83%.

Step 2: (R)-N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred suspension of methanesulfonamide (0.132 g, 1.388 mmol) and potassium tert-butoxide (0.142 g, 1.261 mmol) was added dry N,N-dimethyl formamide (1. mL) at room temperature. Thereupon, (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (0.5 g, 1.261 mmol) was added, and the stirring was continued for 30 min. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (50 mL) and 1M HCl (25 mL). The organic phase was dried over MgSO₄, and then evaporated to dryness. The solid residue was slurried in ethyl acetate. The obtained solid was filtered, washed with ethyl acetate and diethyl ether, respectively, and then dried to, ether, dried to give (R)-N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide as a light brown powder. Yield: 0.28 g, 52%.

¹H NMR (DMSO_(d6)): 11.93 (1H, br s), 11.83 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.19 (1H, dd, J=11.5, 9.3 Hz), 3.79 (1H, dd, J=11.6, 7.8 Hz), 3.49 (2H, m), 3.29 (1H, dd, J=15.9, 9.3 Hz), 3.24 (3H, m), 2.92 (1H, dd, J=8.2, 16.0 Hz).

¹³C NMR (DMSO_(d6)): 168.3, 155.6, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 130, 120.4, 120.3, 120.2, 112.2, 105.9, 105.7, 105.6, 48.5, 41.1, 35.7, 31.5, 29.1.

Example 24: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

Compound was prepared analogous manner to Example 23 from (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 14) and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.93 (1H, br s), 11.78 (1H, s), 7.28 (2H, m), 7.18 (1H, m), 4.23 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 8.0 Hz), 3.74 (1H, dd, J=11.2, 7.6 Hz), 3.50 (2H, s), 3.25 (3H, s), 3.22 (1H, dd, J=15.6, 8.1 Hz), 2.87 (1H, br dd, J=15.6, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 168.3, 159, 157.4, 157.1, 155.7, 155.5, 130.2, 130, 129.9, 129.9, 129.8, 117.1, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.3, 115.1, 115.1, 112.4, 49.3, 41.1, 40.2, 40, 31.5, 29.6.

Example 25: ethyl (R)-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)glycinate

To a stirred mixture of aminoacetic acid ethyl ester hydrochloride (0.070 g, 0.505 mmol) and triethylamine (0.07 mL, 0.505 mmol) in a mixture of dry tetrahydrofuran (2 mL) and dry N,N-dimethyl formamide (0.2 mL) was added (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) (0.1 g, 0.252 mmol). The reaction mixture was stirred for 30 min, and then diluted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and 1N HCl, respectively. After drying over MgSO₄ the solvent was removed under vacuum. Crystallization from diethyl ether afforded the titled compound as a light beige powder. Yield: 0.053 g, 49%.

¹H NMR (DMSO_(d6)): 11.77 (1H, s), 8.38 (1H, t, J=5.9 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.5, 9.2 Hz), 4.07 (2H, q, J=7.0 Hz), 3.82 (2H, d, J=5.9 Hz), 3.78 (1H, dd, J=11.6, 7.9 Hz), 3.32 (2H, m), 3.26 (1H, dd, J=15.9, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz), 1.16 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.7, 168.2, 155.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.2, 120.3, 120.2, 120.1, 113.9, 105.9, 105.7, 105.6, 60.4, 48.4, 40.9, 35.8, 31.1, 29.2, 14.

Example 26: (S)-2-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.14 (1H, d, J=7.5 Hz), 7.85 (1H, m), 7.34 (1H, br s), 7.02 (1H, br s), 4.48 (1H, quin, J=8.6 Hz), 4.17 (2H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.30 (2H, s), 3.26 (1H, dd, J=15.9, 9.3 Hz), 2.88 (1H, dd, J=8.2, 15.9 Hz), 1.19 (3H, d, J=7.2 Hz).

¹³C NMR (DMSO_(d6)): 174.1, 167.3, 155.2, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 48.4, 48.2, 35.8, 31.3, 29.2, 18.3.

Example 27: (R)-N-(cyanomethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.82 (1H, s), 8.66 (1H, br t, J=5.4 Hz), 7.86 (1H, m), 4.49 (1H, quin, J=8.6 Hz), 4.18 (1H, dd, J=11.4, 9.3 Hz), 4.14 (2H, d, J=5.6 Hz), 3.79 (1H, dd, J=11.6, 7.9 Hz), 3.35 (2H, m), 3.26 (1H, br dd, J=15.8, 9.2 Hz), 2.90 (1H, m).

¹³C NMR (DMSO_(d6)): 168.5, 155.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 129.5, 120.3, 120.2, 120.1, 117.6, 113.4, 105.9, 105.7, 105.6, 48.4, 35.8, 30.9, 29.1, 27.2.

Example 28: N-((1r,4R)-4-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.85 (1H, m), 7.82 (1H, d, J=7.7 Hz), 4.48 (1H, quin, J=8.4 Hz), 4.17 (1H, dd, J=9.4, 11.6 Hz), 3.77 (1H, dd, J=7.8, 11.6 Hz), 3.43 (1H, m), 3.34 (1H, m), 3.24 (1H, br dd, J=15.9, 9.3 Hz), 3.20 (2H, s), 2.87 (1H, dd, J=7.8, 15.8 Hz), 1.77 (2H, m), 1.73 (2H, br m), 1.16 (4H, m).

¹³C NMR (DMSO_(d6)): 166.7, 155.1, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 128.7, 120.5, 120.4, 120.3, 114.5, 105.8, 105.7, 105.5, 68.1, 48.4, 47.4, 35.7, 33.9, 31.5, 30.2, 29.3.

Example 29: N-(2-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, m), 7.84 (2H, m), 4.47 (1H, m), 4.17 (1H, m), 3.77 (1H, m), 3.36 (1H, m), 3.32-3.16 (4H, m), 2.89 (1H, m), 2.07-1.0 (8H, several multiplets).

¹³C NMR (DMSO_(d6)): 167.2, 167.2, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.8, 120.5, 120.4, 120.3, 120.3, 120.2, 114.7, 105.9, 105.7, 105.5, 71.1, 54.5, 48.4, 35.7, 33.9, 31.8, 31.7, 30.9, 29.3, 29.2, 24.1, 23.8.

Example 30: (R)-N,N-dimethyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a light khaki powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.84 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.48 (2H, s), 3.23 (1H, dd, J=15.8, 9.4 Hz), 2.98 (3H, s), 2.86 (1H, dd, J=15.8, 8.1 Hz), 2.82 (3H, s).

¹³C NMR (DMSO_(d6)): 167.9, 155.1, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.4, 105.9, 105.7, 105.6, 48.5, 37, 35.8, 35.1, 29.2, 29.1.

Example 31: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid (prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1)) (0.3 g, 0.563 mmol) in tetrahydrofuran (4 mL) was added cc. HCl (1.17 ml, 14.08 mmol) at room temperature and the solution was stirred for 4 h. Thereupon, the solvent was removed under vacuum, the residue was taken up in water (ca. 10 mL) and then the resultant dark insoluble material was filtered off. The filtrate was neutralized to pH 7 by addition of 5 M NaOH, and then aged in ice for 30 min. The precipitate was collected, washed with minimum volume of water and dried in vacuum at 50° C. The crude product was re-slurried in acetone, and then dried to give (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid as a beige powder. Yield: 0.11 g, 45%.

¹H NMR (DMSO_(d6)): 10.4-6.5 (4H, br), 8.31 (1H, br s), 7.84 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, br dd, J=11.1, 9.5 Hz), 3.77 (1H, br dd, J=11.7, 8.0 Hz), 3.54 (1H, m), 3.35 (1H, m), 3.32 (1H, m), 3.31 (2H, m), 3.29 (1H, m), 2.91 (1H, br dd, J=15.7, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 168.8, 168.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.2, 120.3, 120.2, 120.1, 114.3, 105.9, 105.7, 105.6, 54.1, 48.4, 40.3, 35.8, 31.5, 29.1.

Example 32: ((R)-N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred solution of aminocyclopentane (0.05 mL, 0.505 mmol) in dry tetrahydrofuran (2 mL) was added (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) (0.1 g, 0.252 mmol). The reaction was stirred 30 min. at room temperature. Thereupon, the mixture was diluted with ethyl acetate (ca. 10 mL), washed with a solution of sodium bicarbonate, 1 M HCl, respectively. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. Crystallization from a mixture of diethyl ether-petroleum ether afforded (R)-N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide as a beige powder. Yield: 0.064 g, 61%.

¹H NMR (DMSO_(d6)): 11.74 (1H, br s), 7.93 (1H, br d, J=7.0 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.3 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.25 (1H, br dd, J=15.8, 9.2 Hz), 3.21 (2H, s), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, dq, J=12.7, 6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 155.1, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.8, 120.5, 120.4, 120.3, 114.6, 105.9, 105.7, 105.5, 50.5, 48.4, 35.7, 32.2, 32.2, 31.5, 29.3, 23.4.

Example 33: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Step 1: tert-butyl (1S,5R)-4-(3-((tert-butoxycarbonyl)amino)-3-oxopropanoyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of tert-butyl (1S,5R)-1-(3,5-difluorophenyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 2.148 mmol) (Example 1 Step 10) and tert-butyl carbamate (0.252 g, 2.148 mmol) in acetonitrile (20 mL) was stirred under reflux for 3 h. The mixture was then evaporated to dryness and chromatographed twice (dichloromethane-methanol, and then petroleum ether-ethyl acetate). The product was isolated as a light yellow oil. (Yield: 0.33 g, 27%).

Step 2: 3-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanamide hydrochloride

A solution of tert-butyl (1S,5R)-4-(3-((tert-butoxycarbonyl)amino)-3-oxopropanoyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.33 g, 0.687 mmol) in 4 M HCl (1.37 mL, 5.49 mmol) in dioxane was stirred at room temperature for 4 h. The resulting precipitate was filtered off, washed with diethyl ether and dried under vacuum to give the product as a white solid. (Yield: 0.125 g, 52%).

Step 3: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide)

A solution of 3-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanamide hydrochloride (0.117 g, 0.369 mmol), potassium thiocyanate (0.0395 g, 0.406 mmol) and 6 M HCl (0.015 mL, 0.185 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was stirred under reflux for 2 h. Thereupon, the mixture was cooled to room temperature and ethanol was evaporated. The residue was partitioned between water and dichloromethane and then the organic phase was dried over MgSO₄, filtered and evaporated. Chromatography in a mixture of dichloromethane-methanol afforded the titled product as a light yellow solid. Yield: 0.031 g, 25%.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 7.36 (1H, br s), 7.10 (3H, m), 7.05 (1H, br s), 4.18 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.2 Hz), 3.25 (2H, m), 2.93 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 163.4, 163.3, 161.8, 161.7, 156.1, 145, 144.9, 144.9, 131.9, 113.7, 110, 110, 109.9, 109.8, 102.3, 102.1, 101.9, 50.8, 36.1, 31.2, 25.1, 23.

Example 34: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxocyclopentyl)acetamide

To a stirred suspension of (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) (100 mg, 0.257 mmol) in dry tetrahydrofuran (2 mL) was added di(1H-imidazol-1-yl)methanone (50 mg, 0.308 mmol) and the mixture was stirred for 1 h. Thereupon, 2-aminocyclopentanone hydrochloride (77 mg, 0.565 mmol) and the reaction mixture was stirred for additional 1 h. The mixture was then diluted with ethyl acetate (5 mL), washed with 1 M HCl solution. The organic phase was dried (MgSO₄), filtered and stripped down to dryness under vacuum. The crude product was purified by chromatography in a mixture of dichloromethane-methanol (9:1). The thus obtained oil was crystalized by trituration in n-heptane (light brown powder). Yield: 68 mg, 56%.

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 8.18, 8.17 (1H, 2 d, J=3.4 Hz), 7.73 (1H, m), 7.17 (1H, m), 4.43 (1H, m), 4.15 (1H, dd, J=9.5, 11.3 Hz), 4.03 (1H, m), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.28 (2H, t, J=5.1 Hz), 3.22 (1H, m), 2.86 (1H, m), 2.24 (1H, 2 m), 2.18-2.04 (2H, m), 1.91 (1H, m), 1.81-1.66 (2H, m).

¹³C NMR (DMSO_(d6)): 214.8, 214.8, 167.5, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.3, 129.2, 118.7, 118.7, 118.6, 118.5, 118.5, 118.4, 113.9, 113.9, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 56.3, 48.5, 35.7, 35.6, 35.5, 31.2, 29.3, 28.7, 28.7, 17.9.

Example 35: (5aS,6aR)-1-(2-aminoethyl)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

To a stirred solution of 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide (Example 33) (52 mg, 0.162 mmol) in dry tetrahydrofuran (1 mL), was added sodium borohydride (0.032 g, 0.809 mmol) at room temperature, and then the mixture was cooled to 0° C. A solution of boron trifluoride diethyl etherate (0.103 ml, 0.809 mmol) in dry tetrahydrofuran (0.5 ml) was added dropwise to the above mixture, whereupon the reaction was allowed to warm up to room temperature and stirred for 2 h. Thereupon, the reaction was cooled again to 0° C. and quenched with 1 M HCl (˜0.3 mL), followed by addition of 2 M HCl (˜0.2 mL, to pH=1). The mixture was then allowed to warm up to room temperature and heated at reflux for 30 min. Thereupon, the mixture was cooled to room temperature, diluted with water, and then tetrahydrofuran was evaporated off. The aqueous phase was extracted with dichloromethane, whereupon, the organic phase was dried over MgSO₄, filtered and evaporated to dryness to give the product as a yellow solid. Yield: 0.037 g, 60%).

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 7.77 (3H, br s), 7.13 (1H, tt, J=2.3, 9.3 Hz), 7.11 (2H, m), 4.19 (1H, d, J=12.2 Hz), 4.00 (1H, d, J=12.2 Hz), 3.05 (2H, m), 2.97 (1H, dd, J=8.2, 4.4 Hz), 2.71 (2H, m), 1.69 (1H, dd, J=8.3, 5.2 Hz), 1.24 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 163.4, 163.3, 161.8, 161.7, 156.8, 144.9, 144.8, 144.8, 132.1, 114.1, 110.2, 110.1, 110, 110, 102.4, 102.2, 102, 50.8, 37.5, 36.3, 24.9, 22.5, 22.4.

Example 36: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile Step 1: (1S,5R)-tert-butyl 4-(2-cyanoacetyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a cooled mixture (−78° C.) of acetonitrile (0.357 ml, 6.79 mmol) and dry tetrahydrofuran (10 mL) was added 1.6 N n-butyllithium (6.19 ml, 9.90 mmol) dropwise. The mixture was stirred in the cold for 30 min., and then a solution of (1R,5S)-3-tert-butyl 2-methyl 5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2 g, 5.66 mmol) (Example 4, step 1) in anhydrous tetrahydrofuran (5 mL) was added, dropwise. The reaction mixture was stirred in the cold for 3 h, and then quenched by addition of 1 M HCl (9.90 ml, 9.90 mmol. Thereupon, the mixture was and allowed to warm up to room temperature and the pH of the mixture was adjusted to 3 by addition of 1 M HCl. The mixture was then partitioned between diethyl ether and brine, the organic phase was separated, dried over MgSO₄, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 9:1, 4:1, then 2:1). (Yield: 1.31 g, 57%).

Step 2: 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanenitrile hydrochloride

A mixture of (1S,5R)-tert-butyl 4-(2-cyanoacetyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3 g, 3.59 mmol) and a solution of 4 M HCl in dioxane (17.94 mL, 71.7 mmol) was was stirred at room temperature for 4 h. Diethyl ether was then added and the mixture was stirred for 15 min. The resulting yellow solid was filtered off and dried under vacuum. (Yield: 0.96 g, 81%).

Step 3: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile

To a solution of 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanenitrile hydrochloride (950 mg, 3.18 mmol) in a mixture of ethanol (13 mL) and water (13 mL) was added potassium thiocyanate (340 mg, 3.50 mmol) followed by addition of cc HCl (0.131 ml, 1.590 mmol). The solution was heated at reflux for 1 h. and then cooled to room temperature. Thereupon, ethanol was evaporated off, and the aqueous phase was extracted with dichloromethane. The organic phase was separated and evaporated to dryness. Chromatography (dichloromethane-methanol (98:2, then 95:5) afforded the product as a yellow foam. (Yield: 0.35 g, 32%).

¹H NMR (DMSO_(d6)): 12.06 (1H, s), 7.29 (2H, m), 7.22 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.91 (2H, m), 3.82 (1H, d, J=12.0 Hz), 2.90 (1H, dd, J=8.4, 4.3 Hz), 1.72 (1H, dd, J=8.4, 5.5 Hz), 1.23 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.6, 157.4, 157.2, 157, 132.5, 128.3, 128.3, 128.2, 128.2, 117.2, 117.1, 117.1, 117, 117, 117, 116.1, 116, 115.9, 115.9, 108.8, 51.6, 51.6, 32.7, 21.9, 20.5, 13.4.

Example 37: N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide Step 1: (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred mixture of ethyl potassium malonate (3.39 g, 19.89 mmol) in dry tetrahydrofuran (43 mL) was added magnesium bromide diethyl etherate (3.42 g, 13.26 mmol), at room temperature under inert atmosphere, and then the thus obtained white suspension was heated at 50° C. for 3 h (1^(st) mixture).

In parallel, 1,1′-carbonyldiimidazole (3.66 g, 22.54 mmol) was added, in portions to a light yellow solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Example 4 step 1) (4.5 g, 13.26 mmol) in dry tetrahydrofuran (35 mL) at 0° C., under nitrogen. The thus obtained yellow solution was allowed to warm up to room temperature, stirred for 2 h, and then added to the 1^(st) suspension at room temperature dropwise. Thereupon, the reaction was stirred at room temperature for 24 h, and the mixture was quenched with sodium hydrogen sulfate. The aqueous phase was extracted with a mixture of ethyl acetate-petroleum ether (2:1). The combined organic phases were washed with saturated solution of sodium bicarbonate, dried over MgSO₄, filtered and evaporated to dryness. Chromatography (ethyl acetate-petroleum ether; 9:1, then 4:1) gave the product as a light oil. (Yield: 3.52 g, 61%).

Step 2: (1S,5R)-tert-butyl 4-(3-(benzyl(methyl)amino)-3-oxopropanoyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 2.442 mmol) in toluene (4 mL) was added N-methylbenzylamine (0.63 ml, 4.88 mmol) followed by addition of N,N-dimethylpyridin-4-amine (0.090 g, 0.733 mmol) at room temperature. The solution was heated at 100° C. for 20 h, whereupon cooled to room temperature, diluted with a mixture of ethyl acetate-petroleum ether (1:1) and washed with 1M HCl. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The thus obtained yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 4:1, then 2:1) to leave the product as a yellow oil. (Yield: 0.88 g, 67%).

Step 3: N-benzyl-3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-N-methyl-3-oxopropanamide hydrochloride

A mixture of (1S,5R)-tert-butyl 4-(3-(benzyl(methyl)amino)-3-oxopropanoyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (870 mg, 1.796 mmol) and 4 M HCl in dioxane (6.7 mL, 26.9 mmol) was stirred at room temperature for 2 h. Diethyl ether was then added and the suspension was stirred for 15 min. The resulting off-white precipitate was filtered and dried under vacuum. (Yield: 0.57 g, 67%).

Step 4: N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

To a stirred solution of N-benzyl-3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-N-methyl-3-oxopropanamide hydrochloride (556 mg, 1.321 mmol) in a mixture of ethanol (5.4 mL) and water (5.4 mL) was added potassium thiocyanate (0.141 mg, 1.453 mmol) followed by addition of cc. HCl (0.054 mL, 0.661 mmol). The solution was heated at reflux for 1 h, and then cooled to room temperature. Thereupon, ethanol was evaporated off and the aqueous phase was extracted with dichloromethane. The organic phase was then dried over MgSO₄, filtered and evaporated to dryness to give the product as a light yellow semi-solid. (Yield: 0.17 g, 29%).

¹H NMR (DMSO_(d6)): 11.70 (0.65H, s), 1.68 (0.35H, s), 7.38 (0.7H, t, J=7.8 Hz), 7.34-7.17 (7.3H, m), 4.64 (0.7H, s), 4.53 (1.3H, m), 4.09, 4.08 (1H, 2 d, J=12 Hz), 3.81, 3.79 (1H, 2 d, J=12 Hz), 3.69-3.58 (2H, m), 2.98 (1.95H, s), 2.81 (1.05H, s), 2.76 (0.35H, dd, J=8.4, 4.3 Hz), 2.72 (0.65H, dd, J=8.3, 4.2 Hz), 1.63 (1H, m), 1.11 (0.65H, t, J=4.8 Hz), 1.09 (0.35H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.3, 158.8, 158.6, 157.2, 157, 155.9, 137.5, 137.1, 131.8, 131.7, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 127.7, 127.3, 127.1, 126.8, 117.2, 117.1, 117, 117, 117, 116.9, 116.8, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 113.9, 52.6, 51.5, 50.2, 35, 33.

Example 38: N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow foam.

¹H NMR (DMSO_(d6)): 11.62 (1H, 2 s), 7.29 (1H, td, J=9.4, 4.6 Hz), 7.25 (1H, ddd, J=9.1, 5.9, 3.2 Hz), 7.20 (1H, m), 4.08 (1H, d, J=11.9 Hz), 3.81 (1H, d, J=12.2 Hz), 3.53 (2H, m), 3.29 (2H, m), 2.99 (1.65H, s), 2.82 (1.35H, s), 2.79, 2.78 (1H, 2 dd, J=8.3, 4.1 Hz), 1.65 (1H, dd, J=8.4, 5.3 Hz), 1.52 (0.9H, m), 1.43 (1.1H, m), 1.30 (0.9H, m), 1.24 (1.1H, m), 1.11 (1H, m), 0.92 (1.35H, t, J=7.4 Hz), 0.87 (1.65H, t, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 158.8, 158.6, 157.2, 157, 155.8, 131.7, 131.6, 128.7, 128.6, 128.6, 128.5, 117.2, 117.1, 117, 117, 116.8, 115.9, 115.9, 115.8, 115.7, 114.1, 114, 51.5, 49.1, 46.8, 35.1, 33.2, 32.4, 30, 29.5, 28.9, 28.9, 22.3, 22.2, 20.9, 20.8, 19.5, 19.4, 1.

Example 39: (5aS,6aR)-1-(2-(butyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide (Example 37) and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.81 (1H, br s), 9.25 (1H, br s), 7.30 (1H, m), 7.27 (1H, m), 7.22 (1H, m), 4.08 (1H, br d, J=12.2 Hz), 3.81 (1H, d, J=12.0 Hz), 3.17 (2H, br m), 2.95 (2H, m), 2.93 (1H, dd, J=8.2, 4.2 Hz), 2.81 (2H, br m), 2.69 (3H, br s), 1.67 (1H, br dd, J=8.2, 5.3 Hz), 1.57 (2H, br m), 1.31 (2H, dq, J=14.9, 7.4 Hz), 1.18 (1H, br t, J=4.7 Hz), 0.91 (3H, t, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.7, 157.2, 157.1, 156.5, 131.6, 128.6, 128.5, 128.5, 128.4, 117.2, 117.2, 117.1, 117, 117, 116.8, 116, 116, 115.9, 115.8, 55.1, 53.5, 51.5, 39.8, 32.6, 26, 22.2, 20.5, 19.8, 19.5, 13.6.

Example 40: (5aS,6aR)-1-(2-(benzyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide (Example 37) and isolated as a white foam.

¹H NMR (CDCl₃): 10.33 (1H, br s), 7.37 (2H, t, J=7.3 Hz), 7.33 (2H, t, J=8.5 Hz), 7.29 (1H, t, J=7.3 Hz), 7.05 (1H, td, J=9.1, 4.5 Hz), 7.00-6.93 (2H, m), 4.25 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.3 Hz), 3.57 (2H, m), 2.67 (4H, m), 2.51 (1H, dd, J=8.2, 4.1 Hz), 2.28 (3H, s), 1.58 (1H, dd, J=8.2, 5.5 Hz), 1.12 (1H, m).

¹³C NMR (CDCl₃): 159.3, 158.9, 157.6, 157.2, 155.8, 137.5, 130.3, 129.4, 128.6, 128.1, 128.1, 128, 128, 127.5, 119.3, 117.1, 117, 116.9, 116.8, 116.7, 116.7, 116.5, 116.5, 116, 115.9, 115.8, 115.8, 62.8, 55.8, 52.1, 52.1, 41.5, 32.7, 22.3, 21.2, 20.9.

Example 41: (5aS,6aR)-1-((1H-tetrazol-5-yl)methyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile (Example 36) (50 mg, 0.165 mmol) in dry toluene (1 mL) was added dibutyltin oxide (41.0 mg, 0.165 mmol) followed by addition of azidotrimethylsilane (0.044 mL, 0.330 mmol). The reaction mixture was heated at 100° C. for 24 h. The mixture was then cooled to room temperature, partitioned between diethyl ether and 1 M sodium hydroxide (1.6 mL) and the aqueous phase was washed with diethyl ether. The ethereal phase was discarded and the aqueous phase was acidified with 2 M HCl to pH=1. The resulting solid was collected by filtration, washed with water and dried under vacuum. (Yield: 25 mg, 37%).

¹H NMR (DMSO_(d6)): 11.85 (1H, s), 7.29 (1H, td, J=9.4, 4.5 Hz), 7.25 (1H, ddd, J=9.0, 5.9, 3.2 Hz), 7.21 (1H, m), 4.18 (2H, m), 4.10 (1H, br d, J=12.0 Hz), 3.80 (1H, br d, J=5.7 Hz), 2.69 (1H, dd, J=8.3, 4.2 Hz), 1.63 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.6, 157.2, 157, 156.8, 153.1, 132.4, 128.5, 117.2, 116.9, 115.9, 51.6, 32.6, 22, 20.5, 19.3.

Example 42: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 8 from ethyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.65 (1H, br s), 7.28 (2H, m), 7.20 (1H, m), 4.75 (1H, t, J=5.3 Hz), 4.06 (1H, br d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.60 (2H, m), 2.88 (1H, dd, J=8.2, 4.1 Hz), 2.55 (2H, m), 1.61 (1H, dd, J=8.1, 5.4 Hz), 1.14 (1H, t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.6, 157.2, 157, 155.7, 130.9, 128.9, 128.8, 128.7, 128.7, 117.2, 117.1, 117, 117, 116.9, 116.9, 116.8, 116.7, 116.7, 115.9, 115.8, 115.7, 115.6, 59.4, 51.4, 51.4, 32.4, 28, 22.5, 20.6.

Example 43: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic acid Step 1: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (Example 44, step 9) (1.4 g, 4.28 mmol) in isopropyl acetate (7 mL) was added sodium borohydride (0.259 g, 6.84 mmol) at 0-5° C. followed by addition of boron trifluoride etharate (1.084 mL, 8.55 mmol. The mixture was stirred for 2 h in the cold, then quenched with 0.5 M sodium hydroxide (30.8 mL, 15.4 mmol), and allowed to stir at room temperature for 30 min. The organic phase was separated, dried over MgSO₄, evaporated to dryness to leave a yellowish oil. Yield: 1.37 g, 97%).

Step 2: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.46 g, 1.468 mmol) in dry dichloromethane (14 mL) was added Dess-Martin periodinane (3-oxo-1λ⁵-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (0.623 g, 1.468 mmol) in one portion to give a clear solution. Thereupon, the mixture was stirred at room temperature for 3 h, concentrated to approximately one third and subjected to chromatography (petroleum ether-ethyl acetate 9:1, then 4:1). The product was isolated as yellowish oil. (Yield: 1.21 g, 94%).

Step 3: ((4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (1.2 g, 3.85 mmol) in a mixture of tetrahydrofuran (10 mL) and water (5 mL) was added potassium cyanide (0.301 g, 4.63 mmol) followed by addition of cc HCl (0.319 ml, 3.85 mmol). The mixture was stirred for 8 h, then extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO₄ and evaporated to dryness to give (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate as a yellowish oil. (Yield: 1.44 g, 99%).

Step 4: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate

A mixture of (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (1.43 g, 3.80 mmol) and 2 M HCl (28.5 ml, 57.1 mmol) was stirred under reflux for 16 h. After cooling to room temperature the mixture was filtered through a celite plug to remove insoluble coloured stuff and then the filtrate was evaporated to dryness under vacuum. The residue was azeotroped twice with dry ethanol and the residue was taken up in abs. ethanol (20 mL). The thus obtained solution was treated with 4 M HCl (9.51 ml, 38.0 mmol) in dioxane and stirred under reflux for 2 h. The mixture was evaporated to dryness, and then azeotroped with abs. ethanol. The resulting semisolid was taken up in abs. ethanol (30 mL), neutralized by addition of triethylamine to pH=6-7, then a second crop of triethylamine (0.530 ml, 3.80 mmol) was added followed by addition of di-tert-butyl dicarbonate (0.830 g, 3.80 mmol). The reaction was allowed to stir at room temperature for 2 h, and then evaporated to dryness at 40° C. The residue was partitioned between dichloromethane and water, the organic phase was dried over MgSO₄ and concentrated under reduced pressure. Chromatography (petroleum ether-ethyl acetate; 9:1, then 4:1) gave the product as a yellow oil. (Yield: 1.16 g, 79%).

Step 5: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.15 g, 2.98 mmol) in dry dichloromethane (25 mL) was added Dess-Martin periodinane (3-oxo-1λ⁵-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (1.266 g, 2.98 mmol) at room temperature in one portion and the mixture was stirred for 2 h. The reaction mixture was concentrated under vacuum, whereupon the reside was purified by chromatography (petroleum ether-ethyl acetate; 4:1). The product was isolated as a yellowish oil. (1.08 g, 94% yield).

Step 6: ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate (0.4 g, 1.043 mmol) in 4 M HCl (5.22 mL, 20.87 mmol) in dioxane was stirred at room temperature for 4 h. The reaction mixture was diluted with a mixture of diethyl ether (20 mL) and petroleum ether (5 mL) and stirred for 30 min, Thereupon, the resulting precipitate was collected, washed with diethyl ether, petroleum ether and dried under vacuum at 50° C. to give ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride as a white powder. (Yield: 0.34 g, 92%).

Step 7: (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate

A solution of ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride (0.33 g, 1.032 mmol), 6 M HCl (0.086 ml, 0.516 mmol) and potassium thiocyanate (0.110 g, 1.135 mmol) in a mixture of ethanol (5 mL) and water (5 mL) was stirred under reflux for 30 min. The reaction was then cooled to room temperature, and the resulting solid was collected, washed with a mixture of ethanol and water (1:1), and dried under vacuum at 50° C. to give (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate as a white solid. (Yield: 0.28 g, 84%).

Step 8: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic acid

To a stirred solution of (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate (0.08 g, 0.247 mmol) in methanol (2 ml) was added 5 M sodium hydroxide (0.148 ml, 0.740 mmol) at room temperature and the solution was stirred for 24 h. The mixture was then diluted with water (2 mL) and a second crop of 5 M sodium hydroxide (0.148 ml, 0.740 mmol) was added and the mixture was stirred for 48 h, Methanol was removed under vacuum, the residue was diluted with water (ca. 5 mL), and then acidified to pH=2 by adding 6 M HCl. The precipitate was collected, washed with water and dried under vacuum at 50° C. to give (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic acid as white powder. (Yield: 0.052 g, 71%).

¹H NMR (DMSO_(d6)): 12.95 (1H, br s), 12.49 (1H, s), 7.16 (3H, m), 4.28 (1H, dd, J=11.1, 8.3 Hz), 4.20 (1H, quin, J=8.6 Hz), 3.76 (1H, dd, J=11.0, 8.8 Hz), 3.47 (1H, dd, J=16.7, 8.1 Hz), 3.10 (1H, dd, J=16.7, 9.3 Hz).

¹³C NMR (DMSO_(d6)): 163.3, 163.2, 161.7, 161.6, 159.5, 158.9, 145, 145, 144.9, 140.4, 112.6, 110.9, 110.9, 110.8, 110.8, 102.8, 102.6, 102.4, 50.8, 45.7, 32.3.

Example 44: ethyl 2-(5a-(thiophen-2-yl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 4 from 3-(tert-butoxycarbonyl)-5-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as an orange foam.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.44 (1H, dd, J=5.1, 1.3 Hz), 7.11 (1H, dd, J=3.6, 1.2 Hz), 7.00 (1H, dd, J=5.1, 3.6 Hz), 4.16 (1H, d, J=12.0 Hz), 4.10 (2H, q, J=7.2 Hz), 4.00 (1H, d, J=12.0 Hz), 3.55 (2H, m), 2.68 (1H, dd, J=8.4, 4.0 Hz), 1.83 (1H, dd, J=8.4, 5.6 Hz), 1.24 (1H, dd, J=5.4, 4.5 Hz), 1.20 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 156.4, 143.6, 132.2, 127.5, 125.1, 124.7, 112.3, 60.7, 52.2, 32.7, 29.7, 24.9, 24.3, 14.1.

Example 45: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde Step 1: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-(methylsulfinyl)acetyl)pyrrolidine-1-carboxylate

To a solution of dimethyl sulfoxide (0.543 mL, 7.64 mmol) in dry tetrahydrofuran (5 mL) was added 1.6 M methyllithium (4.77 mL, 7.64 mmol) in diethyl ether with external ice-water bath cooling. The mixture was allowed to warm up to room temperature and stirred for 40 min. Thereupon, a solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (Example 1 step 9) (0.5 g, 1.528 mmol) and di(1H-imidazol-1-yl)methanone (0.248 g, 1.528 mmol) in dry tetrahydrofuran (5 mL) was added dropwise with external ice-water bath cooling and the mixture was allowed to warm up to rim temperature and stir under nitrogen for 30 min. The mixture was then cooled 0° C. and neutralized by adding 2 M HCl (3.82 ml, 7.64 mmol) to pH=4-5. Followed by addition of brine. The mixture was extracted with a mixture of ethyl acetate-petroleum ether (2:1) and the organic phase was dried over MgSO₄ and evaporated to dryness to give the product as a yellowish oil. (Yield: 0.44 g, 74%).

Step 2: 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-(methylsulfinyl)ethanone hydrochloride

A stirred mixture of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-(methylsulfinyl)acetyl)pyrrolidine-1-carboxylate (0.43 g, 1.110 mmol) and 4 M HCl (5.55 mL, 22.20 mmol) in dioxane was stirred at room temperature for 2 h. The mixture was then diluted with a mixture of diethyl ether-petroleum ether, aged for 30 min, the supernatant liquid was decanted from the separated oil which solidified on standing under high vacuum to give 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-(methylsulfinyl)ethanone hydrochloride. (Yield: 0.32 g, 89%).

Step 3: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde

A solution of 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-(methylsulfinyl)ethanone hydrochloride (0.31 g, 0.957 mmol), 6 M HCl (0.080 ml, 0.479 mmol) and potassium thiocyanate (0.099 g, 1.019 mmol) in a mixture of ethanol (4 mL) and water (4 mL) was stirred under reflux for 30 min. Thereupon, the reaction was cooled to room temperature, diluted with water, the resultant solid was filtered off and the mother liqueur was extracted with dichloromethane. The organic phase was dried over MgSO₄, and evaporated to dryness. The residue was combined with the first precipitate and then recrystallised from ethyl acetate to give (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde as a beige powder. (Yield: 0.035 g, 13%).

¹H NMR (DMSO_(d6)): 12.76 (1H, br s), 9.36 (1H, s), 7.18 (3H, m), 4.31 (1H, dd, J=8.4, 10.8 Hz), 4.26 (1H, q, J=8.4 Hz), 3.81 (1H, dd, J=10.8, 8.1 Hz), 3.63 (1H, dd, J=16.8, 8.0 Hz), 3.25 (1H, dd, J=16.8, 8.9 Hz).

¹³C NMR (DMSO_(d6)): 175.9, 163.4, 163.3, 161.7, 161.6, 160.8, 145.8, 144.9, 144.8, 144.8, 121.2, 111, 111, 110.9, 110.8, 102.9, 102.8, 102.6, 51, 45.7, 31.4.

Example 46: (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

To a stirred solution of (S)-ethyl 6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate (analogous to Example 43, step 7) (0.08 g, 0.222 mmol) in dry diethyl ether (2 mL) and dry tetrahydrofuran (1 mL) was added dropwise 2.4 M suspension of lithium aluminumhydride (0.102 ml, 0.244 mmol) in tetrahydrofuran with external ice-water bath cooling. The reaction was stirred in the cold for 30 min, then quenched with 2 M HCl to pH=1-2. Thereupon, the mixture was diluted with dichloromethane (ca. 5 mL), the insoluble material was collected, washed with water and dichloromethane, respectively. The wet filter cake was dissolved in a mixture of ethanol and dichloromethane with heating, and then filtered. The filtrate was evaporated to dryness to give (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white solid. (Yield: 0.026 g, 36%).

¹H NMR (DMSO_(d6)): 11.85 (1H, br s), 7.86 (1H, m), 5.07 (1H, br t, J=5.1 Hz), 4.50 (1H, quin, J=8.5 Hz), 4.21 (2H, br d, J=4.7 Hz), 4.18 (1H, br dd, J=11.4, 9.4 Hz), 3.78 (1H, dd, J=11.6, 7.6 Hz), 3.33 (1H, m), 2.96 (1H, br dd, J=15.8, 8.0 Hz).

¹³C NMR (DMSO_(d6)): 155.6, 146.4, 146.3, 146.3, 145.3, 145.2, 144.7, 143.7, 143.6, 128.8, 120.5, 120.4, 120.4, 120.3, 105.9, 105.7, 105.6, 53.1, 48.4, 35.7, 29.

Example 47: (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Step 1: (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid (0.5 g, 1.376 mmol) (analogous to Example 44, step 9) in dry tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanone (0.223 g, 1.376 mmol) at room temperature and the mixture was stirred for 30 min. Thereupon, a solution of 1.6 M methyllithium (4.30 ml, 6.88 mmol) in diethyl ether was added to a solution of dimethyl sulfone (0.648 g, 6.88 mmol) in dry tetrahydrofuran (5 mL) at room temperature and the mixture was stirred for 15 min before addition of the previously prepared imidazolide solution with stirring and ice-water bath cooling. The mixture was stirred for 30 min in the cold, then quenched with 2 M HCl (3.44 ml, 6.88 mmol) and extracted with diethyl ether (ca. 15 mL). The organic phase was dried over MgSO₄) concentrated under reduced pressure and chromatographed (ethyl acetate-petroleum ether; 4:1, then 2:1) to give (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a colourless oil. (Yield: 0.45 g, 74%).

Step 2: 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone hydrochloride

To a stirred solution of (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.41 g, 0.933 mmol) in 4 M HCl (4.67 mL, 18.66 mmol) in dioxane was stirred at room temperature for 3 h. The mixture was then diluted with a mixture of diethyl ether (20 mL) and petroleum ether (5 mL), and aged for 30 min. The thus obtained precipitate was collected, washed with diethyl ether and petroleum ether, and then dried under vacuum at 50° C. to give 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone hydrochloride as a white powder. (Yield: 0.28 g, 80%).

Step 3: (S)-1-((methylsulfonyl)methyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

A solution of 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone hydrochloride (0.27 g, 0.719 mmol), 6 M HCl (0.060 ml, 0.359 mmol) and potassium thiocyanate (0.077 g, 0.790 mmol) in a mixture of ethanol (4 mL) and water (4 mL) was stirred under reflux for 30 min. The mixture was then cooled to room temperature, the resulting solid was collected, washed with water and dried under vacuum at 50° C. to give (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as a white powder. (Yield: 0.21 g, 77%).

¹H NMR (DMSO_(d6)): 12.08 (1H, s), 7.86 (1H, m), 4.57 (1H, quin, J=8.4 Hz), 4.30 (2H, m), 4.23 (1H, dd, J=11.6, 9.2 Hz), 3.83 (1H, dd, J=11.7, 7.5 Hz), 3.38 (1H, dd, J=16.3, 9.4 Hz), 2.99 (1H, dd, J=7.7, 16.4 Hz), 2.97 (3H, s).

¹³C NMR (DMSO_(d6)): 156.6, 146.4, 146.3, 146.3, 145.2, 144.8, 144.7, 144.6, 143.6, 132.9, 120.5, 120.4, 120.3, 108, 105.9, 105.8, 105.6, 50.1, 49, 39.6, 35.6, 29.5.

Example 48: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Step 1 (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3 g, 8.84 mmol) (analogous to Example 44, step 9) in dry dichloromethane (30 mL) was added 1,1′-carbonyldiimidazole (1.720 g, 10.61 mmol) in portions at room temperature under nitrogen and the mixture was stirred for 1 h. Thereupon, N,O-dimethylhydroxylamine hydrochloride (1.035 g, 10.61 mmol) was added in one portion and the resulting suspension was stirred overnight. The mixture was then washed with water, the organic phase was dried over MgSO₄, filtered and evaporated to dryness. The thus obtained light yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 4:1, then 2:1). The product was isolated as a light yellow foam. (Yield: 2.21 g, 59%).

Step 2 (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred ice-cooled mixture of phenethylmagnesium bromide in dry diethyl ether (8 mL) (prepared from (2-Bromoethyl)benzene (0.446 ml, 3.27 mmol) and magnesium turnings (0.165 g, 6.80 mmol)) was added a solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 2.62 mmol) in dry tetrahydrofuran (5 mL) dropwise below 10° C. The reaction mixture was stirred at room temperature for 24 h. The mixture was then cooled to 0° C. and 2 M HCl was added carefully. The phases were separated and organic phase was dried over MgSO₄, filtered and evaporated to dryness. The resulting light yellow oil purified by chromatography (petroleum ether-ethyl acetate; 9:1, 4:1, then 2:1). (Yield: 0.34 g, 30%).

Step 3 1-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-phenylpropan-1-one hydrochloride

A solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (340 mg, 0.795 mmol) in 4 M HCl in dioxane (1.59 mL, 6.36 mmol) was stirred at room temperature for 2 h. The solvent was evaporated off and the thus obtained oil was used without purification. (Yield: 0.289 g, 100%).

Step 4 (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of 1-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-phenylpropan-1-one hydrochloride (289 mg, 0.794 mmol) in a mixture of ethanol (3 mL) and water (3 ml) was added potassium thiocyanate (0.085 mL, 0.874 mmol) followed by addition of cc. HCl (0.033 ml, 0.397 mmol). The solution was heated at reflux and for 30 min. The mixture was then cooled to room temperature and ethanol was evaporated off. The precipitated oil was extracted from the aqueous phase with dichloromethane. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The thus obtained light yellow foam was purified by chromatography (petroleum ether-ethyl acetate; 1:1), then 1:2) to leave a yellow foam. (Yield: 0.11 g, 34%).

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 7.29 (3H, m), 7.20 (5H, m), 4.03 (1H, d, J=12.2 Hz), 3.76 (1H, d, J=12.2 Hz), 2.88 (2H, m), 2.70 (3H, m), 1.53 (1H, dd, J=8.2, 5.3 Hz), 0.96 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.8, 158.6, 158.6, 157.2, 157, 157, 155.7, 140.8, 130.5, 128.8, 128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.2, 126, 118.7, 117.2, 117.1, 117, 117, 116.8, 116.8, 116.7, 116.7, 115.9, 115.8, 115.7, 115.7, 51.3, 51.3, 33.9, 32.4, 25.9, 22.4, 20.5.

Example 49: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(3-phenylpropyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 48 from (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and (3-phenylpropyl)magnesium bromide. The product was isolated as a yellow foam.

¹H NMR (DMSO_(d6)): 11.71 (1H, s), 7.28 (3H, br t, J=6.9 Hz), 7.24-7.14 (4H, m), 4.07 (1H, br d, J=11.9 Hz), 3.79 (1H, d, J=12.0 Hz), 2.85 (1H, dd, J=8.1, 4.2 Hz), 2.61 (2H, br t, J=7.6 Hz), 2.42 (2H, m), 1.91 (2H, m), 1.64 (1H, dd, J=8.1, 5.4 Hz), 1.17 (1H, br t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 158.8, 158.7, 158.7, 157.2, 157.1, 157.1, 155.8, 141.5, 130.2, 128.8, 128.8, 128.7, 128.7, 128.4, 128.3, 125.8, 119.1, 117.2, 117.1, 117, 116.9, 116.9, 116.8, 116.7, 115.9, 115.8, 115.7, 115.6, 51.3, 51.3, 34.4, 32.5, 29.2, 23.6, 22.5, 20.6.

Example 50: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Step 1 (1S,5R)-tert-butyl 4-(cyano(hydroxy)methyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1S,5R)-tert-butyl 1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.500 g, 1.546 mmol) (analogous to Example 39 step 8) in a mixture of tetrahydrofuran (3.4 mL) and water (1.72 mL) was added potassium cyanide (0.121 g, 1.856 mmol) followed by the addition of cc. HCl (0.127 mL, 1.546 mmol). The reaction was stirred at room temperature overnight. The mixture was then extracted with dichloromethane, washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to give the product as a yellow oil. (Yield: 0.554 g, 87%).

Step 2 (1S,5R)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-1-hydroxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of (1S)-tert-butyl 4-(cyano(hydroxy)methyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,554 g, 1,581 mmol) in 2 M HCl (11.86 mL, 23.72 mmol) was refluxed for 20 h. The mixture was then cooled to room temperature and precipitated brown solid was removed by filtration. The filtrate was evaporated to dryness, and then azeotroped twice with ethanol. The thus obtained residue was dissolved in ethanol (9 mL), and then treated with 4 M HCl in dioxane (3.95 mL, 15.81 mmol). The reaction mixture was refluxed for 2 h, wherepon cooled to room temperature and evaporated twice with ethanol. The resulting residue was dissolved in ethanol (11 mL), neutralized to pH=6-7 by addition of triethylamine (0.22 mL, 1,581 mmol) followed by addition of di-tert-butyl dicarbonate (0,345 g, 1,581 mmol). The reaction was stirred at room temperature overnight. Thereupon, the mixture was concentrated under reduced pressure (water bath <40° C.). The residue was quenched with water and extracted with dichloromethane. The organic phase was dried over MgSO₄, filtrated and concentrated. The crude material was purified by chromatography (8% ethyl acetate in petroleum Ether). The product was isolated as a pale yellow oil. (Yield: 0.21 g, 33%).

Step 3 ethyl 2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate hydrochloride

To a stirred solution of (1S)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-1-hydroxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,210 g, 0,528 mmol) in dichloromethane (5.3 mL) was added Dess-Martin periodinane (3-oxo-1λ⁵-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (0,224 g, 0,528 mmol) at room temperature. The reaction was stirred at room temperature for 4 h. The solvent was then removed under reduced pressure to give a light pink pastel. Chromatography (dichloromethane-methanol-aq. Ammonia) gave the product as a pale yellow oil. (Yield: 0.142 g, 68%).

Step 4 ethyl 2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate hydrochloride

A solution of (1S)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,142 g, 0,359 mmol) in 4 M HCl in dioxane (1,796 mL, 7.18 mmol) was stirred at room temperature for 2.5 h. The mixture was then diluted with a mixture of diethyl Ether (4 mL) and petroleum ether (1 mL), stirred for 30 min, whereupon the volatiles were evaporated off to give the product as a brown oil. (Yield: 0.126 g, 100%).

Step 5 (5aS,6aR)-ethyl 5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-1-carboxylate

To a stirred solution of ethyl 2-((5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate hydrochloride (0,126 g, 0,360 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was added cc. HCl (0.03 mL, 0,180 mmol) and potassium thiocyanate (0,039 g, 0,396 mmol) at room temperature. The reaction mixture was refluxed for 30 min, and then cooled to room temperature. The stirring was continued overnight, and then the resultant off-white precipitate was filtered off, washed with cold water and dried under vacuum. (Yield: 0.79 mg, 65%).

Step 6 (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution (5aS,6aR)-ethyl 5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-1-carboxylate (0,188 g, 0,559 mmol) in a mixture of dry diethyl ether (3.2 mL) and dry tetrahydrofuran (1.6 mL) was added dropwise 2.4 M suspension of lithium aluminum hydride (0,256 mL, 0,615 mmol) in terahydrofuran with ice-water bath cooling. The reaction was stirred for 30 min at 0-5° C., quenched with 0.5 M HCl to pH=1-2 (ca. 5 mL), and then diluted with diethyl ether (ca. 10 mL). The resulting solid was collected, washed with water and dried under vacuum at 50° C. to give a light yellow powder. (Yield: 0.038 g, 22%).

¹H NMR (DMSO_(d6)): 11.75 (1H, br s), 7.11 (3H, m), 5.10 (1H, br s), 4.25 (2H, m), 4.20 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.0 Hz), 3.02 (1H, dd, J=8.3, 4.3 Hz), 1.69 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 163.4, 163.3, 161.8, 161.7, 156.7, 144.9, 144.8, 144.8, 131.4, 119.8, 110, 110, 109.9, 109.8, 102.3, 102.1, 101.9, 53.1, 50.7, 36.3, 25.4, 22.9.

Example 51: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-bromo-2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 12.63 (1H, br s), 11.72 (1H, br s), 7.75 (1H, td, J=8.5, 5.8 Hz), 7.16 (1H, td, J=9.2, 1.0 Hz), 4.04 (1H, d, J=12.2 Hz), 3.74 (1H, br d, J=12.0 Hz), 3.49 (2H, m), 2.77 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.4 Hz), 1.24 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 161.9, 161.9, 160.2, 160.2, 158.8, 158.8, 158.8, 157.2, 157.1, 133.1, 133, 131.9, 117.1, 117, 116.9, 113.5, 113.5, 113.4, 113.3, 113.3, 103.7, 103.7, 103.6, 103.6, 51.5, 29.9, 26.5, 21.8, 21.2.

Example 52: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid.

The product was isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 12.60 (1H, br s), 11.70 (1H, s), 7.45 (1H, dd, J=6.5, 2.5 Hz), 7.42 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.30 (1H, t, J=9.4 Hz), 4.09 (1H, br d, J=12.0 Hz), 3.80 (1H, d, J=12.0 Hz), 3.47 (2H, m), 2.88 (1H, dd, J=8.2, 4.1 Hz), 1.67 (1H, dd, J=8.2, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 161.3, 159.6, 156.1, 132.1, 130.1, 130.1, 129.4, 129.3, 128.9, 128.8, 128.3, 128.3, 117.6, 117.4, 113, 51.6, 32.4, 29.9, 22.2, 20.6.

Example 53: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 12.60 (1H, br s), 11.68 (1H, s), 7.31 (1H, dt, J=8.7, 2.0 Hz), 7.27 (1H, t, J=1.5 Hz), 7.22 (1H, dt, J=9.9, 1.9 Hz), 4.21 (1H, d, J=12.0 Hz), 4.03 (1H, d, J=12.2 Hz), 3.45 (2H, m), 3.00 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.2, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 163.1, 161.5, 156.3, 144.8, 144.7, 134.2, 134.1, 132, 123, 122.9, 114.3, 114.2, 112.9, 112.8, 112.8, 50.8, 36.1, 36.1, 29.9, 25.1, 22.6.

Example 54: ethyl 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as an off-white foam.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.30 (1H, t, J=9.4 Hz), 4.11 (2H, q, J=7.1 Hz), 4.09 (1H, d, J=12.2 Hz), 3.81 (1H, d, J=12.2 Hz), 3.57 (2H, m), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.4 Hz), 1.21 (3H, t, J=7.1 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 161.3, 159.6, 156.2, 132.3, 130.2, 130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 112.3, 60.7, 51.6, 51.6, 32.4, 29.8, 22.1, 20.6, 14.1.

Example 55: ethyl 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.32 (1H, dt, J=8.7, 2.0 Hz), 7.28 (1H, t, J=1.5 Hz), 7.23 (1H, dt, J=9.9, 2.0 Hz), 4.21 (1H, d, J=12.2 Hz), 4.11 (2H, q, J=7.0 Hz), 4.04 (1H, d, J=12.2 Hz), 3.54 (2H, m), 2.99 (1H, dd, J=8.4, 4.4 Hz), 1.70 (1H, dd, J=8.4, 5.3 Hz), 1.21 (3H, t, J=7.0 Hz), 1.15 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 163.1, 161.5, 156.4, 144.7, 144.7, 134.2, 134.1, 132.3, 123, 123, 114.4, 114.2, 112.9, 112.8, 112.1, 60.7, 50.9, 36.1, 36.1, 29.8, 25, 22.7, 14.1.

Example 56: (2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred solution of 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 52) (630 mg, 1.860 mmol) in anhydrous dichloromethane (11 mL) was added 1,1′-Carbonyldiimidazole (362 mg, 2.232 mmol) and the reaction was stirred for 30 min. at room temperature. Thereupon, ammonia (0.53 mL, 3.72 mL) 7 M in methanol was added and the mixture was stirred for 3 h at room temperature. The solvent was then evaporated and the obtained brown oil was separated by column chromatography (dichloromethane-methanol). Trituration in a mixture of dichloromethane-diethyl ether-petroleum ether afforded the titled product as a dark yellow solid.

¹H NMR (DMSO_(d6)): 11.64 (1H, s), 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.37 (1H, br s), 7.30 (1H, t, J=9.5 Hz), 7.03 (1H, m), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.27 (2H, m), 2.85 (1H, dd, J=8.4, 4.3 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 161.2, 159.6, 155.9, 131.8, 130.1, 130.1, 129.3, 129.3, 129, 128.9, 128.3, 128.3, 117.6, 117.4, 114, 51.6, 32.3, 31.2, 22.1, 20.7.

Example 57: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 56 from 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 51). The product was isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.67 (1H, m), 7.74 (1H, td, J=8.4, 5.9 Hz), 7.39 (1H, br s), 7.15 (1H, td, J=9.2, 1.2 Hz), 7.04 (1H, br s), 4.02 (1H, d, J=12.2 Hz), 3.72 (1H, d, J=12.2 Hz), 3.29 (2H, m), 2.74 (1H, dd, J=8.4, 4.4 Hz), 1.64 (1H, dd, J=8.2, 5.4 Hz), 1.28 (1H, br t, J=4.9 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 161.9, 161.9, 160.2, 160.2, 158.8, 158.8, 157.2, 157.1, 155.8, 133, 133, 131.5, 117.2, 117.1, 117, 114.4, 113.5, 113.5, 113.4, 113.3, 103.7, 103.7, 103.6, 103.6, 51.4, 31.2, 26.4, 21.7, 21.3.

Example 58: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 56 from 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 53). The product was isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.62 (1H, s), 7.35 (1H, br s), 7.31 (1H, dt, J=8.7, 2.1 Hz), 7.28 (1H, t, J=1.6 Hz), 7.23 (1H, dt, J=10.0, 1.9 Hz), 7.05 (1H, br s), 4.19 (1H, d, J=12.0 Hz), 4.01 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.95 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.19 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 163.1, 161.5, 156.1, 144.9, 144.9, 134.2, 134.1, 131.9, 123, 123, 114.3, 114.1, 113.7, 112.9, 112.8, 50.9, 36.1, 36.1, 31.2, 24.9, 22.8

Example 59: ethyl (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4S)-1-(tert-butoxycarbonyl)-4-(3-bromo-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.81 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.4 Hz), 4.47 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.2, 9.5 Hz), 4.09 (2H, q, J=7.1 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.27 (1H, dd, J=15.8, 9.4 Hz), 2.86 (1H, dd, J=15.8, 7.9 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.1, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.9, 118.9, 118.7, 118.6, 113.8, 113.8, 113.6, 113.6, 112.6, 104.1, 104.1, 103.9, 103.9, 60.7, 48.7, 35.6, 29.8, 29.3, 14.1.

Example 60: ethyl (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(3-bromo-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.81 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.6 Hz), 4.47 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 4.09 (2H, q, J=7.0 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.27 (1H, dd, J=16.0, 9.4 Hz), 2.86 (1H, dd, J=15.9, 8.0 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.1, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.9, 118.9, 118.7, 118.6, 113.8, 113.8, 113.6, 113.6, 112.6, 104.1, 104.1, 103.9, 103.9, 60.7, 48.7, 35.6, 29.8, 29.2, 14.1.

Example 61: ethyl (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,5-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.82 (1H, s), 7.29 (1H, dt, J=4.7, 9.5 Hz), 7.26 (1H, m), 7.19 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.3, 7.9 Hz), 4.09 (2H, q, J=7.0 Hz), 3.74 (1H, dd, J=11.3, 7.5 Hz), 3.53 (2H, m), 3.22 (1H, dd, J=15.5, 8.0 Hz), 2.86 (1H, dd, J=15.5, 7.8 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 159.1, 159, 157.5, 157.5, 157.1, 157.1, 155.6, 155.5, 155.5, 130.1, 130, 130, 129.9, 129.8, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.2, 115.1, 115, 113.1, 60.7, 49.4, 40.3, 29.8, 29.6, 14.1.

Example 62: ethyl (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4S)-1-(tert-butoxycarbonyl)-4-(5-bromo-2-fluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an orange solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, s), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.1, 8.8 Hz), 4.22 (1H, quin, J=7.9 Hz), 4.14 (1H, dd, J=11.2, 8.1 Hz), 4.09 (2H, q, J=7.2 Hz), 3.75 (1H, dd, J=11.3, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.6, 8.2 Hz), 2.87 (1H, dd, J=15.6, 7.9 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 160.3, 158.7, 155.6, 131.9, 131.8, 131.4, 131.3, 130.7, 130.6, 129.7, 118, 117.9, 116.5, 116.5, 113, 60.7, 49.3, 40.4, 29.8, 29.5, 14.1.

Example 63: ethyl (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.83 (1H, s), 7.86 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.19 (1H, dd, J=11.6, 9.1 Hz), 4.09 (2H, q, J=7.2 Hz), 3.79 (1H, dd, J=11.7, 7.6 Hz), 3.51 (2H, s), 3.30 (1H, dd, J=16.0, 9.4 Hz), 2.91 (1H, dd, J=15.9, 7.8 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.1, 155.5, 146.4, 146.3, 146.2, 145.3, 145.2, 144.7, 144.6, 143.7, 143.6, 129.6, 120.5, 120.4, 120.3, 112.7, 105.9, 105.7, 105.6, 60.6, 48.6, 35.7, 29.8, 29.1, 14.

Example 64: ethyl (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(5-chloro-2-fluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a pale yellow solid.

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 7.45 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, dd, J=10.1, 8.9 Hz), 4.22 (1H, quin, J=7.8 Hz), 4.15 (1H, dd, J=11.3, 8.1 Hz), 4.10 (2H, q, J=7.2 Hz), 3.75 (1H, dd, J=11.3, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.6, 7.8 Hz), 1.19 (3H, t, J=7.0 Hz).

¹³C NMR (DMSO_(d6)): 169.1, 159.8, 158.1, 155.6, 130.3, 130.2, 129.7, 128.9, 128.8, 128.5, 128.5, 128.4, 128.4, 117.6, 117.4, 113, 60.7, 49.3, 40.3, 29.8, 29.5, 14.

Example 65: ethyl (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an orange solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, s), 7.41 (1H, tt, J=8.4, 6.6 Hz), 7.13 (2H, m), 4.43 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=9.2, 11.3 Hz), 4.09 (2H, q, J=7.0 Hz), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.50 (2H, s), 3.25 (1H, dd, J=15.7, 9.2 Hz), 2.86 (1H, dd, J=15.7, 8.5 Hz), 1.19 (3H, t, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 169.1, 161.6, 161.5, 160, 159.9, 155.4, 130, 129.8, 129.8, 129.7, 116.6, 116.5, 116.4, 112.6, 112.2, 112.2, 112.1, 112.1, 60.6, 48.7, 35.2, 29.8, 29.3, 14.

Example 66: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a greenish solid.

¹H NMR (DMSO_(d6)): 11.64 (1H, s), 7.45 (1H, dd, J=2.7, 6.5 Hz), 7.43 (1H, ddd, J=8.6, 4.4, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.57 (6H, m), 3.49 (2H, m), 3.46 (2H, m), 2.78 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.11 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.3, 159.6, 156, 131.8, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 113.7, 66, 54.9, 51.6, 45.7, 41.8, 32.4, 29, 22.1, 20.7.

Example 67: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, s), 7.88 (1H, d, J=7.6 Hz), 7.45 (1H, dd, J=2.6, 6.5 Hz), 7.43 (1H, ddd, J=8.5, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.8, 8.8 Hz), 4.07 (1H, d, J=12.0 Hz), 3.83 (1H, oct, J=7.3 Hz), 3.79 (1H, d, J=12.2 Hz), 3.25 (2H, m), 2.80 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz), 1.06 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.7, 161.2, 159.6, 155.8, 131.6, 130.2, 130.1, 129.3, 129.3, 128.9, 128.8, 128.3, 128.3, 117.6, 117.4, 114.1, 51.5, 51.5, 40.7, 32.3, 31.5, 22.4, 22.3, 22, 20.8.

Example 68: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.62 (1H, s), 7.78 (1H, q, J=4.5 Hz), 7.31 (1H, dt, J=8.7, 1.9 Hz), 7.28 (1H, t, J=1.5 Hz), 7.23 (1H, dt, J=10.0, 1.8 Hz), 4.19 (1H, d, J=12.2 Hz), 4.02 (1H, d, J=12.0 Hz), 3.27 (2H, m), 2.93 (1H, dd, J=8.3, 4.3 Hz), 2.60 (3H, d, J=4.5 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.2, 163.1, 161.4, 156.2, 144.9, 144.8, 134.2, 134.1, 132, 123, 123, 114.3, 114.1, 113.4, 112.9, 112.8, 50.9, 36, 36, 31.3, 24.9, 22.8.

Example 69: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N,N-dimethylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.58 (1H, s), 7.31 (1H, dt, J=8.7, 2.1 Hz), 7.27 (1H, t, J=1.6 Hz), 7.22 (1H, dt, J=10.0, 2.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.03 (1H, d, J=12.0 Hz), 3.52 (2 H, s), 3.02 (3H, s), 2.90 (1H, dd, J=8.4, 4.4 Hz), 2.85 (3H, s), 1.68 (1H, dd, J=8.3, 5.2 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.9, 163.1, 161.5, 156.1, 144.8, 144.8, 134.2, 134.1, 131.6, 122.9, 122.9, 114.3, 114.1, 113.8, 112.9, 112.7, 50.8, 37, 36, 36, 35.1, 29.2, 25.1, 22.8.

Example 70: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.61 (1H, s), 7.59-7.53 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.48 (2H, m), 3.46 (2H, t, 6.9 Hz), 3.31 (2H, t, J=6.9 Hz), 2.79 (1H, dd, J=8.4, 4.3 Hz), 1.90 (2H, quin, J=6.9 Hz), 1.78 (2H, quin, J=6.9 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.10 (1H, t br, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 161.8, 160.1, 155.9, 133, 133, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 51.6, 46.1, 45.6, 32.2, 30.5, 25.6, 24, 22.1, 20.7.

Example 71: (R)-N-(3-(dimethylamino)propyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a yellowish powder.

¹H NMR (DMSO_(d6)): 11.78 (1H, m), 10.33 (1H, br s), 8.22 (1H, br t, J=5.5 Hz), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.19 (1H, br t, J=10.3 Hz), 3.80 (1H, m), 3.29 (3H, m), 3.11 (2H, q, J=6.4 Hz), 3.01 (2H, m), 2.91 (1H, br dd, J=15.7, 8.2 Hz), 2.71 (6H, d, J=4.5 Hz), 1.79 (2H, m).

¹³C NMR (DMSO_(d6)): 168.1, 146.4, 146.4, 146.3, 145.4, 145.4, 145.3, 145.3, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.8, 143.7, 143.7, 143.7, 143.6, 143.6, 129.5, 120.3, 120.2, 119.2, 114.7, 105.9, 105.8, 105.6, 54.4, 48.5, 42, 42, 35.9, 35.8, 31.5, 29.2, 24.1.

Example 72: (R)-N-(2-hydroxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 10.98 (1H, m), 7.98 (1H, br t, J=5.2 Hz), 7.84 (1H, m), 4.68 (1H, br s), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, br dd, J=11.2, 9.5 Hz), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.39 (2H, br t, J=5.9 Hz), 3.25 (3H, m), 3.11 (2H, q, J=5.9 Hz), 2.89 (1H, br dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 155.2, 146.4, 146.3, 146.3, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 59.7, 48.4, 41.7, 35.8, 31.5, 29.1.

Example 73: (R)-N-(2-methoxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, br s), 8.04 (1H, br t, J=5.1 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=9.5, 11.3 Hz), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.33 (2H, t, J=5.4 Hz), 3.29-3.16 (8H, m), 2.88 (1H, br dd, J=15.9, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.6, 70.5, 57.8, 48.4, 38.6, 35.7, 31.4, 29.2.

Example 74: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale brown solid.

¹H NMR (DMSO_(d6)): 11.71 (1H, s), 7.93 (1H, br d, J=7.0 Hz), 7.57 (1H, dd, J=6.7, 2.4 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd, J=10.3, 8.8 Hz), 4.20 (1H, quin, J=7.8 Hz), 4.12 (1H, dd, J=11.2, 8.1 Hz), 3.97 (1H, sxt, J=6.9 Hz), 3.73 (1H, dd, J=11.3, 7.5 Hz), 3.21 (2H, s), 3.17 (1H, br dd, J=15.5, 8.1 Hz), 2.83 (1H, dd, J=15.5, 7.8 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

¹³C NMR (DMSO_(d6)): 167, 160.3, 158.7, 155.2, 131.9, 131.8, 131.4, 131.3, 130.8, 130.7, 128.8, 118, 117.9, 116.5, 116.5, 114.8, 50.5, 49.2, 40.3, 32.2, 31.5, 29.7, 23.4.

Example 75: 2-((R)-6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a green solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 8.22 (1H, br d, J=6.5 Hz), 7.45 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=10.1, 8.9 Hz), 4.21 (2H, m), 4.13 (1H, dd, J=11.3, 8.1 Hz), 3.77 (1H, m), 3.72 (2H, m), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.7 Hz), 3.25 (2H, s), 3.18 (1H, dd, J=15.4, 8.1 Hz), 2.84 (1H, dd, J=15.4, 7.8 Hz), 2.07 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 159.8, 158.2, 155.3, 130.4, 130.3, 129, 128.9, 128.8, 128.5, 128.5, 128.5, 128.4, 117.6, 117.4, 114.6, 72.4, 66.3, 49.8, 49.2, 40.3, 32, 31.3, 29.6.

Example 76: (R)-N-cyclopentyl-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale grey solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.92 (1H, br d, J=7.2 Hz), 7.40 (1H, m), 7.13 (2H, m), 4.41 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=9.3, 11.3 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.71 (1H, dd, J=11.4, 8.4 Hz), 3.20 (2H, s), 3.18 (1H, dd, J=9.2, 15.6 Hz), 2.84 (1H, dd, J=15.6, 8.6 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

¹³C NMR (DMSO_(d6)): 167, 161.6, 161.6, 160, 159.9, 155.1, 129.8, 129.7, 129.7, 129, 116.6, 116.4, 116.3, 114.5, 112.2, 112.2, 112.1, 112.1, 50.5, 48.6, 35.3, 32.2, 32.2, 31.5, 29.4, 23.4.

Example 77: 2-((R)-6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale grey solid.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 8.21 (1H, br d, J=6.5 Hz), 7.40 (1H, m), 7.13 (2H, t, J=8.1 Hz), 4.41 (1H, quin, J=8.8 Hz), 4.21 (1H, m), 4.14 (1H, dd, J=10.8, 9.8 Hz), 3.76 (1H, m), 3.71 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.19 (1H, dd, J=15.6, 9.2 Hz), 2.84 (1H, dd, J=15.7, 8.7 Hz), 2.06 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 161.6, 161.6, 160, 159.9, 155.1, 129.8, 129.7, 129.7, 129.2, 116.5, 116.4, 116.3, 114.2, 112.2, 112.2, 112.1, 112.1, 72.4, 66.3, 49.8, 48.6, 35.3, 32, 31.3, 29.4.

Example 78 (: (R)-N-cyclopropyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.04 (1H, br d, J=3.7 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.5, 9.3 Hz), 3.77 (1H, dd, J=11.7, 7.9 Hz), 3.25 (1H, dd, J=15.8, 9.4 Hz), 3.19 (2H, m), 2.88 (1H, dd, J=15.9, 8.2 Hz), 2.59 (1H, tq, J=7.4, 3.8 Hz), 0.60 (2H, m), 0.38 (2H, m).

¹³C NMR (DMSO_(d6)): 168.7, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.5, 48.4, 35.7, 31.3, 29.2, 22.4, 5.6, 5.6.

Example 79: (R)-N-(cyclopropylmethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, s), 8.05 (1H, br t, J=5.4 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.6, 9.1 Hz), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.25 (1H, dd, J=9.3, 11.7 Hz), 3.24 (2H, s), 2.92 (2H, t, J=6.2 Hz), 2.89 (1H, dd, J=16.1, 8.3 Hz), 0.87 (1H, m), 0.38 (2H, m), 0.13 (2H, m).

¹³C NMR (DMSO_(d6)): 167.4, 155.2, 146.4, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 48.4, 43.1, 35.8, 31.5, 29.2, 10.7, 3.2.

Example 80: (R)-N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.16 (2H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.24 (1H, br dd, J=15.8, 9.2 Hz), 3.20 (2H, s), 2.87 (1H, br dd, J=15.8, 8.1 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

¹³C NMR (DMSO_(d6)): 166.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.5, 48.4, 44, 35.7, 31.4, 30.2, 30.2, 29.2, 14.6.

Example 81: (R)-1-(4-methylpiperazin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.4, 9.3 Hz), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.50 (2H, m), 3.48-3.38 (4H, m), 3.24 (1H, br dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 2.26 (4H, m), 2.17 (3H, s).

¹³C NMR (DMSO_(d6)): 166.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.5, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 54.6, 54.2, 48.5, 45.6, 45.1, 41.2, 35.8, 29.2, 29.1.

Example 82: (R)-1-(4-hydroxypiperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, br s), 7.85 (1H, m), 4.75 (1H, s br), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, m), 3.86 (1H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.67 (2H, m), 3.49 (2H, m), 3.24 (1H, br dd, J=15.8, 9.2 Hz), 3.16 (1H, m), 3.01 (1H, m), 2.86 (1H, dd, J=15.8, 7.9 Hz), 1.69 (2H, m), 1.32 (1H, br d, J=9.1 Hz), 1.24 (1H, m).

¹³C NMR (DMSO_(d6)): 66.2, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.2, 114.4, 105.9, 105.7, 105.5, 65.4, 65.4, 48.4, 42.8, 39, 35.8, 34.5, 34.4, 33.8, 29.2, 29.1, 29.1.

Example 83: (R)-1-(4-(hydroxymethyl)piperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, br d, J=5.1 Hz), 7.85 (1H, m), 4.48 (1H, m), 4.48 (1H, br), 4.34 (1H, br d, J=11.6 Hz), 4.17 (1H, m), 3.84 (1H, br d, J=12.5 Hz), 3.77 (1H, m), 3.48 (2H, m), 3.23 (3H, m), 2.98 (1H, m), 2.86 (1H, m), 2.52 (1H, m), 1.74-1.51 (3H, m), 0.98 (2H, m).

¹³C NMR (DMSO_(d6)): 166.1, 166.1, 155.2, 155.1, 146.4, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.5, 128.9, 120.4, 120.3, 120.2, 114.5, 114.4, 105.9, 105.7, 105.5, 65.5, 65.5, 48.5, 45.3, 45.3, 41.3, 38.3, 38.3, 35.8, 35.7, 29.2, 29.2, 29, 28.3, 28.3.

Example 84: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.55 (1H, br s), 7.93 (1H, br d, J=7.2 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.6, 10.5 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.73 (1H, dd, J=11.5, 8.0 Hz), 3.21 (1H, m), 3.20 (2H, s), 2.83 (1H, br dd, J=15.8, 8.1 Hz), 1.76 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

¹³C NMR (DMSO_(d6)): 166.9, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 128.9, 118.8, 118.7, 118.6, 116, 115.9, 114.5, 113.2, 113.2, 113.1, 113.1, 50.5, 48.5, 35.6, 32.2, 32.2, 31.5, 29.3, 23.4.

Example 85: (R)-N,N-dimethyl-2-(4-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, m), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.2, 9.5 Hz), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.44 (4H, m), 3.24 (1H, br dd, J=15.8, 9.5 Hz), 3.16 (2H, s), 2.99 (3H, s), 2.86 (1H, dd, J=7.8, 15.7 Hz), 2.80 (3H, s), 2.41 (4H, m).

¹³C NMR (DMSO_(d6)): 168.7, 166.4, 155.2, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 59.5, 52.5, 52.1, 48.5, 45.2, 41.3, 36.6, 35.8, 34.9, 29.2, 29.

Example 86: (R)-1-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperidine-4-carboxamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, br d, J=4.5 Hz), 7.85 (1H, quin, J=8.7 Hz), 7.28 (1H, br s), 6.80 (1H, br s), 4.49 (1H, quin, J=8.4 Hz), 4.30 (1H, br d, J=13.1 Hz), 4.18 (1H, dd, J=9.7, 11.3 Hz), 3.86 (1H, br d, J=11.9 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.50 (2H, m), 3.24 (1H, ddd, J=15.7, 9.1, 6.5 Hz), 3.02 (1H, m), 2.87 (1H, dd, J=7.9, 15.7 Hz), 2.60 (1H, m), 2.32 (1H, tt, J=11.4, 3.8 Hz), 1.69 (2H, m), 1.47 (1H, m), 1.35 (1H, m).

¹³C NMR (DMSO_(d6)): 175.9, 175.9, 166.3, 166.2, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.5, 48.4, 44.8, 41.2, 41, 35.8, 29.1, 29.1, 29, 28.7, 28.1.

Example 87: (R)-1-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, m), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 3.90 (4H, s), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.53 (2H, s), 3.49 (4H, m), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 1.63 (2H, m), 1.55 (2H, br s).

¹³C NMR (DMSO_(d6)): 166.4, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129.1, 120.5, 120.4, 120.3, 114.3, 106.3, 105.8, 105.7, 105.5, 63.8, 48.4, 43.4, 35.8, 34.9, 34.3, 29.2, 29.

Example 88: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, br s), 7.86 (1H, br d, J=7.5 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.80 (1H, m), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.21 (1H, dd, J=9.2, 15.8 Hz), 3.19 (2H, s), 2.84 (1H, dd, J=15.8, 8.3 Hz), 1.03 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.5, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 128.9, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.5, 113.2, 113.2, 113.1, 113.1, 48.5, 40.6, 35.6, 31.5, 29.3, 22.3.

Example 89: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(3-morpholinopropyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.93 (1H, br t, J=5.5 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.2, 9.4 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.53 (4H, br t, J=4.5 Hz), 3.22 (2H, s), 3.21 (1H, m), 3.06 (2H, m), 2.84 (1H, dd, J=15.8, 8.4 Hz), 2.29 (4H, br s), 2.24 (2H, br t, J=7.2 Hz), 1.53 (2H, quin, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.7, 129, 118.7, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.3, 113.3, 113.2, 113.1, 113.1, 66.2, 55.8, 53.3, 48.5, 37.1, 35.6, 31.5, 29.3, 25.9.

Example 90: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.22 (1H, d, J=6.6 Hz), 7.72 (1H, td, J=8.4, 5.7 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.20 (1H, m), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.76 (1H, m), 3.72 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.6 Hz), 3.24 (2H, s), 3.21 (1H, dd, J=9.3, 15.7 Hz), 2.83 (1H, dd, J=15.6, 8.1 Hz), 2.06 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.7, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.4, 66.3, 49.8, 48.6, 35.6, 32, 31.3, 29.3.

Example 91: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream solid.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.4 Hz), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.49 (2H, m), 3.43 (4H, m), 3.20 (1H, dd, J=15.8, 9.3 Hz), 2.81 (1H, dd, J=15.8, 8.0 Hz), 2.26 (4H, m), 2.17 (3H, s).

¹³C NMR (DMSO_(d6)): 166.5, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.2, 118.9, 118.7, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.6, 54.2, 48.6, 45.6, 45.1, 41.2, 35.7, 29.3, 29.1.

Example 92: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-butyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 11.71 (1H, br s), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, m), 4.15 (1H, dd, J=9.4, 11.3 Hz), 3.72 (1H, dd, J=11.5, 7.8 Hz), 3.47 (2H, m), 3.24 (3H, m), 2.95 (1.6H, s), 2.82 (1H, m), 2.79 (1.4H, s), 1.49 (1H, quin, J=7.6 Hz), 1.40 (1H, m), 1.31-1.15 (2H, m), 0.90, 0.85 (3H, 2 t, J=7.2 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 167.5, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129.2, 129.1, 118.8, 118.8, 118.7, 118.7, 118.6, 118.6, 114.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.1, 48.6, 46.7, 35.7, 35, 33.1, 30, 29.4, 29.3, 29.3, 28.9, 28.8, 19.5, 19.3, 13.7.

Example 93: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.96 (1H, br t, J=5.5 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.67 (1H, br s), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.5, 11.4 Hz), 3.72 (1H, dd, J=11.5, 8.1 Hz), 3.39 (2H, br t, J=5.7 Hz), 3.24 (2H, m), 3.21 (1H, dd, J=15.7, 9.5 Hz), 3.11 (2H, q, J=6.0 Hz), 2.84 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.7, 48.5, 41.7, 35.7, 31.5, 29.2.

Example 94: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 8.03 (1H, br d, J=3.5 Hz), 7.72 (1H, td, J=8.4, 5.9 Hz), 7.16 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.6, 11.2 Hz), 3.72 (1H, dd, J=11.4, 8.1 Hz), 3.21 (1H, dd, J=9.7, 15.9 Hz), 3.18 (2H, s), 2.83 (1H, dd, J=15.6, 8.3 Hz), 2.59 (1H, m), 0.59 (2H, m), 0.38 (2H, m).

¹³C NMR (DMSO_(d6)): 168.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.6, 31.3, 29.3, 22.4, 5.6, 5.6.

Example 95: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.04 (1H, t, J=5.5 Hz), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.24 (2H, s), 3.22 (1H, dd, J=9.5, 15.7 Hz), 2.92 (2H, t, J=6.2 Hz), 2.84 (1H, dd, J=15.7, 8.2 Hz), 0.87 (1H, m), 0.37 (2H, m), 0.13 (2H, m).

¹³C NMR (DMSO_(d6)): 167.4, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 43.1, 35.6, 31.5, 29.3, 10.7, 3.2.

Example 96: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.72 (1H, td, J=8.4, 5.7 Hz), 7.37 (1H, br s), 7.17 (1H, m), 7.02 (1H, br s), 4.45 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=9.5, 11.2 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.23 (1H, dd, J=9.3, 16.0 Hz), 3.21 (2H, d, J=4.8 Hz), 2.85 (1H, dd, J=15.7, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 169.8, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 118.7, 118.5, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.7, 31.2, 29.2.

Example 97: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-propylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.91 (1H, br t, J=5.5 Hz), 7.72 (1H, ddd, J=8.8, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.23 (2H, s), 3.20 (1H, dd, J=9.0, 15.8 Hz), 2.99 (2H, m), 2.83 (1H, dd, J=15.8, 8.3 Hz), 1.39 (2H, sxt, J=7.2 Hz), 0.82 (3H, t, J=7.4 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 40.5, 35.7, 31.5, 29.3, 22.3, 11.4.

Example 98: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 7.85 (1H, m), 5.18-4.57 (1H, 2 br s), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, br t, J=10.3 Hz), 4.0-3.86 (1H, 2 m), 3.78 (1H, br dd, J=11.5, 7.8 Hz), 3.67-3.18 (7H, multiplets), 2.87 (1H, br dd, J=15.7, 7.9 Hz), 2.01-1.68 (4H, m).

¹³C NMR (DMSO_(d6)): 166.8, 166.7, 155.1, 155, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 129, 120.5, 120.4, 120.3, 114.6, 114.1, 105.8, 105.7, 105.5, 62.6, 60.9, 58.8, 58.8, 48.4, 47, 45.5, 35.8, 35.7, 30.7, 30, 29.2, 27.8, 26.7, 23.4, 21.4.

Example 99: (S)-N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.16 (2H, m), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 3.20 (2H, s), 2.87 (1H, dd, J=15.8, 8.1 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

¹³C NMR (DMSO_(d6)): 166.5, 155.2, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.3, 114.3, 105.9, 105.7, 105.6, 48.4, 44, 35.7, 31.4, 30.2, 30.2, 29.2, 14.6.

Example 100: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.97 (0.35H, br s), 4.71 (0.65H, br s), 4.45 (1H, m), 4.15 (1H, dd, J=9.0, 11.2 Hz), 3.95 (0.35H, m), 3.91 (0.65H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.57 (0.35H, m), 3.52-3.36 (3.65H, m), 3.31-3.14 (3H, m), 2.83 (1H, m), 1.84 (4H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155, 155, 132.5, 132.4, 129.3, 129.1, 118.9, 118.8, 118.7, 118.7, 114.5, 114, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 62.7, 60.9, 58.8, 58.8, 48.6, 48.6, 47, 45.5, 35.6, 30.7, 30.1, 29.4, 29.3, 27.8, 26.7, 23.4, 21.4.

Example 101: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.42 (2H, m), 3.41 (2H, s), 3.27 (2H, t, J=6.9 Hz), 3.21 (1H, dd, J=15.7, 9.4 Hz), 2.81 (1H, dd, J=15.7, 8.1 Hz), 1.87 (2H, m), 1.76 (2H, m).

¹³C NMR (DMSO_(d6)): 166.1, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 118.9, 118.8, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 46.2, 45.5, 35.6, 30.5, 29.3, 25.6, 24.

Example 102: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (2H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.20 (1H, dd, J=9.3, 15.5 Hz), 3.19 (2H, s), 2.82 (1H, dd, J=15.6, 8.3 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

¹³C NMR (DMSO_(d6)): 166.5, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 44, 35.6, 31.4, 30.2, 30.2, 29.3, 14.7.

Example 103: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.04 (1H, br t, J=5.4 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.32 (2H, t, J=5.6 Hz), 3.24 (2H, m), 3.22-3.17 (3H, m), 3.20 (3H, s), 2.83 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 70.5, 57.8, 48.5, 38.6, 35.6, 31.5, 29.3.

Example 104: (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.1 Hz), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.42 (4H, m), 3.27 (2H, t, J=7 Hz), 3.25 (1H, dd, J=9.3, 15.8 Hz), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.88 (2H, m), 1.76 (2H, m).

¹³C NMR (DMSO_(d6)): 166.1, 155.1, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 48.5, 46.1, 45.5, 35.7, 30.4, 29.2, 25.6, 24.

Example 105: (S)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.5, 9.2 Hz), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.42 (4H, m), 3.27 (2H, t, J=7 Hz), 3.25 (1H, dd, J=9.3, 15.8 Hz), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.87 (2H, m), 1.76 (2H, m).

¹³C NMR (DMSO_(d6)): 166.1, 155.1, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 48.5, 46.1, 45.5, 35.7, 30.4, 29.2, 25.6, 24.

Example 106: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 8.70 (1H, br d, J=5.1 Hz), 8.25 (1H, br s), 8.12 (1H, br t, J=5.6 Hz), 7.71 (2H, m), 7.62 (1H, m), 7.23 (1H, m), 4.41 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.4, 11.4 Hz), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.47 (2H, m), 3.21 (2H, m), 3.15 (1H, dd, J=15.8, 9.2 Hz), 3.07 (2H, t, J=6.6 Hz), 2.79 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 168, 160.2, 160.1, 158.6, 158.5, 156.6, 156.6, 155.9, 155.8, 155.2, 155.2, 155, 154.9, 143.7, 143.2, 129.8, 129.7, 129.4, 126.3, 123.9, 118.7, 118.5, 118.4, 116.1, 116, 114.1, 114, 113.3, 113.1, 48.5, 38.1, 35.6, 34.3, 31.5, 29.2.

Example 107: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.04 (1H, br t, J=5.6 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.73 (1H, dd, J=11.6, 8.1 Hz), 3.32 (2H, t, J=5.5 Hz), 3.26-3.15 (5H, m), 3.20 (3H, s), 2.84 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 155.1, 129.7, 129.6, 129.1, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 114.2, 113.2, 113.2, 113.1, 113.1, 70.5, 57.8, 48.5, 38.6, 35.6, 31.5, 29.2.

Example 108: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.73 (1H, br s), 7.62 (1H, m), 7.37 (1H, br s), 7.22 (1H, m), 7.01 (1H, br s), 4.45 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.4, 11.2 Hz), 3.74 (1H, dd, J=11.5, 8.1 Hz), 3.23 (1H, dd, J=9.3, 15.7 Hz), 3.21 (2H, m), 2.86 (1H, dd, J=15.7, 8.5 Hz).

¹³C NMR (DMSO_(d6)): 169.8, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 155, 154.9, 129.7, 129.6, 129.2, 118.7, 118.6, 118.4, 116.1, 116, 115.9, 115.9, 114.4, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 31.2, 29.2.

Example 109: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.81 (1H, s), 8.51 (1H, t, J=5.9 Hz), 8.48 (1H, dd, J=0.6, 2.4 Hz), 8.41 (1H, dd, J=4.7, 1.6 Hz), 7.65 (1H, m), 7.62 (1H, m), 7.31 (1H, ddd, J=0.8, 4.8, 7.8 Hz), 7.22 (1H, m), 4.42 (1H, quin, J=8.7 Hz), 4.29 (2H, m), 4.14 (1H, dd, J=9.4, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.32 (2H, m), 3.14 (1H, dd, J=15.7, 9.2 Hz), 2.76 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.9, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 148.8, 148.1, 135.2, 134.7, 129.7, 129.7, 129.3, 123.3, 118.6, 118.5, 118.4, 116.1, 116, 115.9, 115.9, 114, 113.3, 113.2, 113.1, 113.1, 48.5, 39.8, 35.6, 31.4, 29.2.

Example 110: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.71 (1H, br s), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.2, 9.5 Hz), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.42 (2H, m), 3.41 (2 H, s), 3.27 (2H, t, J=6.9 Hz), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz), 1.87 (2H, m), 1.76 (2H, m).

¹³C NMR (DMSO_(d6)): 166.1, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 129.2, 118.9, 118.8, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 113.2, 113.2, 113.1, 113.1, 48.6, 46.1, 45.5, 35.6, 30.4, 29.3, 25.6, 24.

Example 111: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.68 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.57 (2H, s), 3.56 (4H, m), 3.23 (1H, dd, J=15.8, 9.3 Hz), 2.83 (1H, dd, J=15.7, 8.1 Hz), 2.02 (2H, m), 1.91 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.6, 129.4, 124.3, 122.7, 121.1, 118.9, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114, 113.2, 113.2, 113.1, 113.1, 48.6, 42.1, 42.1, 42.1, 38.5, 38.4, 38.4, 35.6, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.2, 28.9.

Example 112: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.77 (1H, s), 8.09 (1H, d, J=7.6 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.93 (1H, m), 3.73 (1H, dd, J=11.7, 8.0 Hz), 3.27-3.17 (5H, m), 3.08 (2H, m), 2.85 (1H, dd, J=15.8, 8.2 Hz), 2.04 (2H, m), 1.90 (2H, m).

¹³C NMR (DMSO_(d6)): 167.1, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.6, 129.2, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 113.3, 113.2, 113.1, 113.1, 48.5, 48.3, 43.9, 35.6, 31.4, 29.3, 29.1.

Example 113: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.79 (1H, s), 8.64 (1H, br t, J=6.3 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=11.2, 9.3 Hz), 3.90 (2H, qd, J=9.8, 6.5 Hz), 3.74 (1H, dd, J=11.5, 8.0 Hz), 3.36 (2H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.84 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 168.6, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.7, 129.4, 127.5, 125.6, 123.8, 121.9, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.5, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 31.1, 29.2.

Example 114: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.20 (1H, t, J=5.6 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.74 (1H, dd, J=11.7, 8.1 Hz), 3.46 (2H, m), 3.27 (2H, m), 3.24 (2H, t, J=6.9 Hz), 3.23 (1H, m), 2.99 (3H, s), 2.87 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 168.1, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 129.5, 118.6, 118.5, 118.4, 116.1, 115.9, 113.8, 113.2, 113.1, 53, 48.5, 40.8, 35.6, 33, 31.3, 29.2.

Example 115: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 10.88 (1H, br s), 8.28 (1H, br t, J=5.3 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.45 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=9.4, 11.4 Hz), 3.75 (1H, dd, J=8.2, 11.5 Hz), 3.64 (2H, br s), 3.46 (2H, q, J=5.9 Hz), 3.33 (2H, m), 3.24 (1H, dd, J=9.2, 15.8 Hz), 3.20 (2H, br s), 3.15 (2H, br s), 2.88 (1H, dd, J=15.8, 8.5 Hz), 2.46-2.24 (4H, 2brs).

¹³C NMR (DMSO_(d6)): 168.5, 160.2, 160.1, 158.5, 158.5, 156.6, 155.3, 155, 129.8, 129.7, 129.6, 118.6, 118.5, 118.4, 116.2, 116.1, 116.1, 116, 113.8, 113.3, 113.3, 113.1, 113.1, 54.2, 48.7, 48.5, 35.6, 33.9, 31.5, 30.4, 29.3.

Example 116: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.22 (1H, d, J=6.6 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.21 (1H, m), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.76 (1H, m), 3.71 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.22 (1H, dd, J=9.4, 15.8 Hz), 2.83 (1H, dd, J=15.8, 8.1 Hz), 2.06 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.7, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.4, 66.3, 49.7, 48.6, 35.6, 32, 31.3, 29.3.

Example 117: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, s), 7.72 (1H, ddd, J=9.0, 8.0, 5.7 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.56 (6H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz), 2.02 (2H, m), 1.91 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.4, 124.2, 122.6, 121, 118.8, 118.7, 118.6, 114, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.6, 42.1, 42.1, 42.1, 38.5, 38.4, 38.4, 35.7, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.3, 28.9.

Example 118: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.19 (1H, t, J=5.7 Hz), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.73 (1H, dd, J=11.6, 8.2 Hz), 3.46 (2H, m), 3.30-3.18 (5H, m), 2.99 (3H, s), 2.86 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 168.1, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.5, 118.6, 118.5, 118.4, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53, 48.5, 40.8, 35.7, 33, 31.3, 29.2.

Example 119: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.95 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.66 (1H, t, J=5.4 Hz), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.39 (2H, q, J=5.9 Hz), 3.24 (2H, m), 3.21 (1H, dd, J=15.8, 9.5 Hz), 3.11 (2H, q, J=6.0 Hz), 2.84 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.7, 48.5, 41.7, 35.7, 31.5, 29.3.

Example 120: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(hydroxymethyl)cyclopentyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, br s), 7.80 (0.5H, d, J=4.5 Hz), 7.80 (0.5H, d, J=4.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, m), 4.32 (1H, m), 4.15 (1H, dd, J=11.1, 9.8 Hz), 4.08 (1H, m), 3.72 (1H, dd, J=11.0, 8.2 Hz), 3.33 (1H, m), 3.27 (2H, s), 3.25 (1H, m), 3.24 (1H, m), 2.84 (1H, m), 1.98 (1H, m), 1.80 (1H, m), 1.65 (2H, m), 1.47 (2H, m), 1.33 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129, 129, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.9, 51.5, 51.5, 48.6, 45, 45, 35.7, 35.6, 31.4, 31.3, 31.3, 29.3, 26.2, 26.2, 21.5.

Example 121: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-hydroxypiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, m), 7.72 (1H, ddd, J=8.7, 8.1, 5.8 Hz), 7.16 (1H, m), 4.89 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, m), 4.08 (0.5H, m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.64-3.43 (4H, m), 3.35 (0.5H, m), 3.26-3.13 (1.5H, m), 3.10 (0.5H, m), 3.00 (0.5H, m), 2.81 (1H, m), 2.57 (0.5H, m), 1.87-1.72 (1H, 2 m), 1.65 (1H, m), 1.44 (0.5H, m), 1.31 (1.5H, m).

¹³C NMR (DMSO_(d6)): 166.7, 166.7, 166.4, 166.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.1, 118.9, 118.8, 118.7, 118.6, 118.6, 118.5, 114.4, 114.3, 114.3, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 65, 64.9, 54.9, 52.3, 48.6, 45.4, 45.4, 41.7, 41.7, 35.7, 32.8, 32.8, 32.3, 32.3, 29.3, 29.2, 29.1, 29, 23.4, 23.4, 21.7, 21.7.

Example 122: tert-butyl (R)-2-((2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)methyl)pyrrolidine-1-carboxylate

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, 2 s), 8.00 (1H, m), 7.72 (1H, td, J=8.4, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.5, 11.4 Hz), 3.72 (1H, dd, J=8.0, 11.5 Hz), 3.71 (1H, m), 3.25 (2H, s), 3.20 (3H, m), 3.07, 2.96 (1H, 2 m), 2.83 (1H, m), 1.87-1.58 (5H, m), 1.38 (9H, s).

¹³C NMR (DMSO_(d6)): 167.8, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.2, 153.9, 153.4, 132.5, 132.4, 129.2, 129, 118.7, 118.6, 118.5, 118.5, 114.3, 114.3, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 78.4, 56.4, 48.5, 46.4, 46.1, 40.9, 35.7, 31.5, 29.3, 28.1, 27.6, 23.1, 22.2.

Example 123: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.48 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 4.01 (1H, br d, J=13.6 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.54 (2H, m), 3.36 (1H, m), 3.21 (1H, m), 3.07 (1H, m), 2.94 (3H, s), 2.82 (1H, m), 2.61 (1H, m), 2.04 (2H, br d, J=12.5 Hz), 1.56 (1H, m), 1.42 (1H, m).

¹³C NMR (DMSO_(d6)): 166.5, 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.3, 129.2, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.4, 58.4, 48.6, 43.9, 37.5, 35.7, 29.2, 29, 29, 24.7, 24.1.

Example 124: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a tan solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, br s), 8.51 (1H, t, J=5.6 Hz), 8.48 (1H, s), 8.41 (1H, d, J=3.7 Hz), 7.73 (1H, m), 7.65 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=7.6, 4.8 Hz), 7.17 (1H, t, J=9.3 Hz), 4.42 (1H, quin, J=8.7 Hz), 4.29 (2H, d, J=5.7 Hz), 4.14 (1H, t, J=10.3 Hz), 3.72 (1H, dd, J=11.3, 8.4 Hz), 3.33 (2H, m), 3.13 (1H, br dd, J=15.7, 9.2 Hz), 2.75 (1H, br dd, J=15.7, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.9, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 148.8, 148.1, 135.1, 134.7, 132.5, 132.4, 129.3, 123.3, 118.6, 118.5, 118.3, 114, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 39.8, 35.6, 31.4, 29.2.

Example 125: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 7.72 (1H, ddd, J=8.7, 8.1, 5.8 Hz), 7.17 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.3, 9.4 Hz), 3.87 (4H, m), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.62 (2H, s), 3.26 (2H, br m), 3.23 (1H, dd, J=15.9, 9.3 Hz), 3.10 (2H, br t, J=4.9 Hz), 2.84 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.5, 118.8, 118.7, 118.6, 113.8, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.3, 51.1, 48.6, 43.8, 40.3, 35.7, 29.2, 28.7.

Example 126: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.69 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.48 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 4.01 (1H, br d, J=13.6 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.54 (2H, m), 3.36 (1H, m), 3.21 (1H, m), 3.07 (1H, m), 2.94 (3H, s), 2.82 (1H, m), 2.61 (1H, m), 2.04 (2H, br d, J=12.5 Hz), 1.56 (1H, m), 1.42 (1H, m).

¹³C NMR (DMSO_(d6)): 166.5, 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.3, 129.2, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.4, 58.4, 48.6, 43.9, 37.5, 35.7, 29.2, 29, 29, 24.7, 24.1.

Example 127: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-1-cyclohexylethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, s), 7.73 (2H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.57 (1H, m), 3.22 (3H, m), 2.81 (1H, dd, J=15.7, 8.2 Hz), 1.64 (4.7H, m), 1.23 (1.3H, m), 1.09 (3H, m), 0.97 (3H, d, J=6.7 Hz), 0.88 (2H, m).

¹³C NMR (DMSO_(d6)): 166.7, 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.8, 118.8, 118.7, 118.6, 114.6, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.7, 48.5, 42.3, 35.6, 31.6, 29.5, 28.8, 28.5, 26, 25.7, 25.7, 17.5.

Example 128: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a green powder.

¹H NMR (DMSO_(d6)): 11.69 (1H, br s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1.6H, m), 4.15 (1H, m), 3.88 (2.4H, m), 3.73 (1H, br dd, J=11.5, 7.8 Hz), 3.57, 3.48 (2H, 2 m), 3.40 (1H, m), 3.34 (1H, m), 3.21 (1H, m), 2.84, 2.71 (3H, 2 s), 2.80 (1H, dd, J=7.4, 15.3 Hz), 1.82-1.61 (2H, m), 1.52 (1H, m), 1.38 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 167.6, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 155, 132.4, 132.4, 129.3, 129.2, 118.9, 118.8, 118.7, 114.4, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66.5, 66.5, 66.2, 49.6, 48.6, 35.7, 30.2, 30.2, 30, 29.5, 29.4, 29.3, 29.2, 27.

Example 129: (R)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.78 (1H, s), 8.10 (1H, d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 3.93 (1H, m), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.28-3.17 (3H, m), 3.26 (2H, s), 3.08 (2H, m), 2.89 (1H, dd, J=8.0, 15.8 Hz), 2.04 (2H, br d, J=11.3 Hz), 1.90 (2H, m).

¹³C NMR (DMSO_(d6)): 167.1, 155.2, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 129, 120.4, 120.3, 120.2, 114.2, 105.9, 105.7, 105.6, 48.4, 48.3, 43.9, 35.7, 31.4, 29.2, 29.1.

Example 130: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.77 (1H, s), 8.09 (1H, d, J=7.6 Hz), 7.72 (1H, ddd, J=8.8, 8.2, 5.9 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.2, 9.5 Hz), 3.93 (1H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.24 (2H, s), 3.22 (3H, m), 3.08 (2H, m), 2.84 (1H, dd, J=15.7, 8.1 Hz), 2.04 (2H, m), 1.90 (2H, m).

¹³C NMR (DMSO_(d6)): 167.1, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.2, 118.8, 118.7, 118.5, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 48.3, 43.9, 35.6, 31.4, 29.3, 29.1.

Example 131: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale brown powder.

¹H NMR (DMSO_(d6)): 11.69 (1H, 2 s), 7.72 (1H, ddd, J=8.6, 8.1, 5.9 Hz), 7.16 (1H, m), 4.87 (0.6H, t, J=5.4 Hz), 4.64 (0.4H, t, J=5.4 Hz), 4.44 (1H, 2 quin, J=8.7 Hz), 4.15 (1H, m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.54 (2H, m), 3.46 (2H, m), 3.40-3.29 (2H, m), 3.20 (1H, m), 3.02 (1.2H, s), 2.82 (1.8H, s), 2.81 (1H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.9, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129.2, 129.1, 118.8, 118.8, 118.7, 118.6, 118.6, 118.5, 114.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.5, 58.4, 51.6, 50, 48.6, 36.4, 35.6, 33.4, 29.4, 29.3, 29.2, 29.1, 29.

Example 132: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.69 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.4 Hz), 4.20 (0.6H, tt, J=3.8, 11.8 Hz), 4.15 (1H, m), 3.72 (1H, br dd, J=11.5, 7.7 Hz), 3.58 (0.4H, tt, J=11.6, 3.5 Hz), 3.51 (0.8H, m), 3.46 (1.2H, m), 3.21 (1H, br dd, J=15.8, 9.3 Hz), 2.80 (1H, m), 2.81, 2.69 (3H, 2 s), 1.84-0.97 (10H, m).

¹³C NMR (DMSO_(d6)): 167.3, 167.3, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 155, 132.4, 132.4, 129.2, 129.1, 118.9, 118.8, 118.8, 114.5, 114.3, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 55.7, 52, 48.6, 35.7, 30.2, 30.2, 30, 29.4, 29.4, 29.3, 29.2, 29.2, 29.2, 26.9, 25.3, 25.1, 25.1, 25, 24.8.

Example 133: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.84 (1H, br d, J=7.5 Hz), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.80 (1H, hep, J=6.7 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.21 (1H, dd, J=9.2, 15.8 Hz), 3.19 (2H, s), 2.83 (1H, dd, J=15.7, 8.2 Hz), 1.04 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 40.6, 35.6, 31.5, 29.4, 22.3.

Example 134: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.76, 1.75 (1H, 2 br s), 8.52 (0.7H, m), 8.49 (0.7H, d, J=1.8 Hz), 8.44 (0.7H, dd, J=4.8, 1.7 Hz), 7.69-7.58 (2H, m), 7.40 (0.3H, dd, J=7.6, 4.9 Hz), 7.33 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.22 (1H, m), 4.65 (0.6H, s), 4.53 (1.4H, m), 4.43 (1H, m), 4.16 (1H, m), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.59 (2H, m), 3.31-3.13 (1H, m), 2.98 (2H, s), 2.79 (1H, s), 2.85-2.73 (1H, m).

¹³C NMR (DMSO_(d6)): 168.4, 155.2, 149.1, 148.7, 148.5, 148.3, 135.4, 134.7, 133.1, 132.7, 129.7, 129.6, 129.3, 129.3, 123.7, 123.5, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 114.1, 113.2, 113.2, 113.1, 113.1, 50.2, 48.5, 48, 35.6, 35.1, 33.4, 29.6, 29.3, 29.2, 29.1.

Example 135: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, 2 quin, J=8.6 Hz), 4.15 (1H, m), 4.06 (0.4H, m), 3.95 (0.6H, m), 3.88 (0.4H, m), 3.83 (0.4H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.70-3.61 (1.8H, m), 3.56 (0.6H, m), 3.52-3.46 (1.4H, m), 3.45 (1H, s), 3.39 (0.4H, m), 3.22 (1H, m), 3.06, 3.06, 3.04, 3.04 (3H, 4 s), 2.84 (1H, m), 2.33 (1H, m), 2.22 (1H, m).

¹³C NMR (DMSO_(d6)): 166.4, 166.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 155.2, 132.5, 132.4, 129.4, 129.4, 118.8, 118.8, 118.7, 118.6, 118.5, 118.5, 113.8, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.6, 60.6, 58.9, 58.9, 48.6, 45.4, 45.4, 45.3, 45.3, 45.1, 44.9, 35.7, 30.3, 30.2, 30.2, 30.2, 29.3, 25.7, 24.1, 24.1.

Example 136: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 7.72 (1H, td, J=8.4, 5.8 Hz), 7.17 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=9.3, 11.1 Hz), 3.87 (4H, m), 3.73 (1H, dd, J=11.5, 7.8 Hz), 3.62 (2H, s), 3.26 (2H, m), 3.23 (1H, dd, J=9.3, 15.8 Hz), 3.10 (2H, m), 2.84 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.5, 118.7, 113.8, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.3, 51.1, 48.6, 43.8, 40.3, 35.7, 29.2, 28.7.

Example 137: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-thiomorpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.2, 9.3 Hz), 3.73 (1H, dd, J=8.0, 11.6 Hz), 3.71 (4H, m), 3.51 (2H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.81 (1H, dd, J=15.9, 8.0 Hz), 2.61 (2H, m), 2.55-2.50 (2H, m).

¹³C NMR (DMSO_(d6)): 166.6, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 48.1, 44, 35.7, 29.3, 29.1, 26.9, 26.4.

Example 138: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-7-azaspiro[4.4]nonan-7-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.71 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.3, 9.4 Hz), 3.81-3.69 (3H, m), 3.59-3.47 (3H, m), 3.44-3.40 (3H, m), 3.36 (1H, m), 3.30-3.18 (2H, m), 2.82 (1H, m), 1.96-1.73 (4H, m).

¹³C NMR (DMSO_(d6)): 166.4, 166.4, 160.8, 159.2, 157.5, 157.5, 155.9, 155.8, 155.1, 132.4, 132.4, 129.3, 118.9, 118.8, 118.7, 114, 114, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 75.2, 75.2, 75.1, 66.9, 66.9, 55, 54.2, 49.6, 48.6, 47.8, 45.6, 45, 35.8, 35.8, 35.8, 35.6, 34.7, 33.2, 30.3, 30.3, 30, 30, 29.3.

Example 139: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.84 (1H, s), 8.58 (1H, t, J=5.9 Hz), 8.50 (1H, m), 7.73 (2H, m), 7.30 (1H, d, J=7.8 Hz), 7.23 (1H, dd, J=6.9, 5.0 Hz), 7.17 (1H, m), 4.43 (1H, quin, J=m), 4.36 (2H, m), 4.14 (1H, dd, J=9.6, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.36 (2H, m), 3.17 (1H, dd, J=15.8, 9.3 Hz), 2.78 (1H, dd, J=15.7, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.9, 160.8, 160.7, 159.1, 159.1, 158.2, 157.5, 157.5, 155.9, 155.9, 155.3, 148.8, 136.7, 132.5, 132.4, 129.2, 122.1, 121.2, 118.6, 118.5, 118.4, 114.1, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.5, 44.3, 35.6, 31.5, 29.2.

Example 140: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.17 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.7, 7.8 Hz), 3.60-3.52 (4H, m), 3.51 (2H, s), 3.48-3.40 (4H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz)

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 48.6, 45.7, 41.7, 35.7, 29.3, 28.9.

Example 141: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.17 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.7, 7.8 Hz), 3.60-3.52 (4H, m), 3.51 (2H, s), 3.48-3.40 (4H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 48.6, 45.7, 41.7, 35.7, 29.3, 28.9.

Example 142: N-(2-(1H-pyrazol-1-yl)ethyl)-2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one (prepared analogous to Example 23 step 1) and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.68 (1H, s), 8.09 (1H, t, J=5.6 Hz), 7.68 (1H, dd, J=2.2, 0.6 Hz), 7.63 (1H, td, J=8.7, 5.6 Hz), 7.43 (1H, dd, J=0.6, 1.8 Hz), 7.21 (1H, dt, J=1.4, 9.2 Hz), 6.20 (1H, m), 4.17 (2H, t, J=6.3 Hz), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.44 (2H, m), 3.31 (2H, m), 2.70 (1H, dd, J=8.4, 4.4 Hz), 1.65 (1H, dd, J=8.2, 5.4 Hz), 1.26 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 168.1, 161.2, 161.2, 159.6, 159.5, 157.8, 157.8, 156.1, 156.1, 155.9, 138.8, 131.5, 130.3, 130.2, 130.1, 117.2, 117.1, 116.9, 115.7, 115.7, 115.6, 115.6, 114, 112.9, 112.9, 112.8, 112.7, 105, 51.4, 50.2, 39.4, 31.3, 26.3, 21.6, 21.2.

Example 143: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.65 (1H, s), 8.03 (1H, br t, J=5.5 Hz), 7.58-7.53 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.30 (2H, m), 2.96 (2H, t, J=6.2 Hz), 2.82 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.15 (1H, t, J=4.8 Hz), 0.90 (1H, m), 0.40 (2H, m), 0.16 (2H, m).

¹³C NMR (DMSO_(d6)): 167.5, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 114, 51.6, 43.2, 31.4, 22, 20.7, 10.7, 3.3, 3.2 Example 144: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 8.66 (1H, br t, J=5.4 Hz), 7.62-7.51 (2H, m), 7.24 (1H, dd, J=10.0, 8.8 Hz), 4.16 (2H, m), 4.09 (1H, dd, J=11.8 Hz), 3.80 (1H, d, J=12.0 Hz), 3.39 (2H, m), 2.85 (1H, dd, J=8.3, 4.2 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.18 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.6, 161.7, 160.1, 156.2, 132.9, 132.9, 132.3, 132.3, 129.3, 129.2, 118, 117.8, 117.6, 116.2, 112.9, 51.6, 32.3, 30.9, 27.3, 22.1, 20.6.

Example 145: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.66 (1H, br s), 8.48 (1H, ddd, J=0.8, 1.8, 4.8 Hz), 8.03 (1H, t, J=5.6 Hz), 7.68 (1H, td, J=7.6, 1.9 Hz), 7.56 (2H, m), 7.24 (2H, m), 7.19 (1H, ddd, J=7.5, 4.9, 1.1 Hz), 4.07 (1H, d, J=12.2 Hz), 3.79 (1H, d, J=12.0 Hz), 3.43 (2H, m), 3.28 (2H, m), 2.88 (2H, t, J=7.3 Hz), 2.79 (1H, dd, J=8.4, 4.3 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.8, 160.1, 159, 156, 149, 136.5, 133, 133, 132.3, 132.3, 131.8, 129.3, 129.2, 123.2, 121.5, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 38.8, 37.2, 32.2, 31.5, 22, 20.7.

Example 146: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(3-(dimethylamino)propyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a dark yellow solid.

¹H NMR (D₂O): 7.52 (1H, dd, J=6.6, 2.3 Hz), 7.43 (1H, m), 7.03 (1H, t, J=9.4 Hz), 4.20 (1H, d, J=12.2 Hz), 3.92 (1H, d, J=12.2 Hz), 3.58 (2H, s), 3.30 (2H, t, J=6.7 Hz), 3.14 (2H, m), 2.87 (6H, s), 2.73 (1H, dd, J=8.4, 4.3 Hz), 1.95 (2H, m), 1.66 (1H, dd, J=8.1, 5.8 Hz), 1.19 (1H, t, J=4.8 Hz).

¹³C NMR (D₂O): 171.6, 162, 160.3, 151.4, 134.7, 133.1, 132.5, 132.4, 128.3, 128.2, 117.6, 117.4, 116.1, 114.3, 55.3, 52.2, 42.7, 36.3, 32.4, 31.3, 24.1, 21.5, 20.5.

Example 147: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 8.11 (1H, dd, J=5.1, 1.2 Hz), 7.68 (1H, br d, J=18.6 Hz), 7.56 (2H, m), 7.23 (1H, dd, J=10.1, 8.8 Hz), 6.99 (1H, br s), 6.75 (1H, br s), 4.08 (1H, br d, J=12.2 Hz), 3.79 (1H, d, J=12.0 Hz), 3.69-3.51 (10H, m), 2.80 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.11 (1H, br t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167, 161.8, 160.1, 156, 133, 133, 132.3, 132.3, 131.8, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.7, 113.2, 51.6, 44.9, 44.6, 44.4, 40.8, 32.3, 29.2, 22.1, 20.7.

Example 148: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige foam.

¹H NMR (DMSO_(d6)): 11.66 (1H, s), 8.23 (1H, d, J=6.7 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=10.1, 8.6 Hz), 4.24 (1H, tt, J=10.2, 3.8 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (2H, m), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.49 (1H, dd, J=8.8, 3.7 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.4, 4.2 Hz), 2.08 (1H, dq, J=12.6, 7.6 Hz), 1.75 (1H, m), 1.66 (1H, dd, J=8.4, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.8, 160.1, 155.9, 133, 133, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.9, 72.4, 66.3, 51.6, 49.8, 32.2, 32, 31.2, 22.1, 20.7.

Example 149: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, br s), 7.63 (1H, td, J=8.7, 5.7 Hz), 7.20 (1H, dt, J=9.3 Hz, 1.3 Hz), 4.04 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.66 (2H, m), 3.59 (4H, m), 2.69 (1H, dd, J=8.4, 4.4 Hz), 2.04 (2H, m), 1.93 (2H, m), 1.68 (1H, dd, J=8.2, 5.4 Hz), 1.24 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156.1, 156, 131.5, 130.3, 130.2, 124.3, 122.7, 121.1, 117.1, 117, 116.9, 115.7, 115.7, 115.6, 115.6, 114, 112.9, 112.9, 112.8, 112.7, 51.4, 42.2, 42.1, 42.1, 38.5, 38.5, 38.4, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.1, 26.4, 21.7, 21.2.

Example 150: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light brown solid.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 8.67 (1H, t, J=6.3 Hz), 7.63 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, dt, J=1.4, 9.2 Hz), 4.03 (1H, d, J=12.2 Hz), 3.93 (2H, qd, J=9.8, 6.5 Hz), 3.74 (1H, d, J=12.2 Hz), 3.43 (2H, m), 2.72 (1H, dd, J=8.4, 4.4 Hz), 1.65 (1H, dd, J=8.4, 5.4 Hz), 1.26 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 169.2, 161.7, 161.6, 160, 160, 158.3, 158.2, 156.6, 156.6, 156.5, 132.2, 130.8, 130.7, 127.9, 126.1, 124.2, 122.4, 117.6, 117.5, 117.4, 116.2, 116.2, 116.1, 116.1, 114, 113.4, 113.4, 113.2, 113.2, 51.9, 40.1, 31.5, 26.8, 22.1, 21.7.

Example 151: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.55-8.48 (2H, m), 8.43 (1H, dd, J=4.7, 1.6 Hz), 7.67 (1H, dt, J=7.8, 2.0 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.34 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.32 (2H, m), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.40 (2H, m), 2.68 (1H, dd, J=8.4, 4.4 Hz), 1.62 (1H, dd, J=8.3, 5.5 Hz), 1.27 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 168, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156, 148.8, 148.1, 135.1, 134.7, 131.6, 130.3, 130.2, 123.4, 117.2, 117, 116.9, 115.7, 115.6, 114, 112.9, 112.9, 112.8, 112.8, 51.4, 39.8, 31.3, 26.3, 21.5, 21.2.

Example 152: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.55-8.48 (2H, m), 8.43 (1H, dd, J=4.7, 1.6 Hz), 7.67 (1H, dt, J=7.8, 2.0 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.34 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.32 (2H, m), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.40 (2H, m), 2.68 (1H, dd, J=8.4, 4.4 Hz), 1.62 (1H, dd, J=8.3, 5.5 Hz), 1.27 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 168, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156, 148.8, 148.1, 135.1, 134.7, 131.6, 130.3, 130.2, 123.4, 117.2, 117, 116.9, 115.7, 115.6, 114, 112.9, 112.9, 112.8, 112.8, 51.4, 39.8, 31.3, 26.3, 21.5, 21.2.

Example 153: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 8.20 (1H, br d, J=7.8 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=9.9, 8.7 Hz), 4.20 (1H, sxt, J=8.1 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.80 (1H, dd, J=8.4, 4.3 Hz), 2.14 (2H, m), 1.90 (2H, m), 1.63 (3H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.6, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 113.9, 51.5, 44.1, 32.2, 31.3, 30.2, 30.2, 22, 20.7, 14.6.

Example 154: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, s), 8.04 (1H, br d, J=3.8 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=11.9 Hz), 3.78 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.81 (1H, dd, J=8.3, 4.2 Hz), 2.62 (1H, m), 1.65 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz), 0.62 (2H, m), 0.42 (2H, m).

¹³C NMR (DMSO_(d6)): 168.8, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 32.2, 31.2, 22.5, 22, 20.7, 5.6, 5.6.

Example 155: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.59 (1H, br s), 7.55 (2H, m), 7.24 (1H, t, J=9.4 Hz), 4.82, 4.28 (1H, 2 m), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.61, 3.52 (2H, 2 m), 2.85, 2.70 (3H, 2 s), 2.77 (1H, m), 1.85-1.40 (9H, m), 1.10 (1H, m).

¹³C NMR (DMSO_(d6)): 167.9, 167.7, 161.7, 160.1, 155.9, 155.9, 133, 132.9, 132.3, 132.2, 131.6, 131.6, 129.3, 129.2, 118, 117.8, 116.2, 116.1, 114.1, 114, 57.6, 53.7, 51.5, 32.3, 32.2, 30.1, 29.5, 29.4, 28.5, 27.8, 27.7, 27.1, 23.9, 23.8, 22.1, 20.7, 20.6.

Example 156: N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 8.45 (1H, t, J=5.9 Hz), 7.47-7.40 (2H, m), 7.35-7.25 (5H, m), 7.22 (1H, m), 4.29 (2H, m), 4.07 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=12.2 Hz), 3.38 (2H, m), 2.77 (1H, dd, J=8.4, 4.3 Hz), 1.62 (1H, dd, J=8.4, 5.3 Hz), 1.16 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 161.2, 159.6, 156, 139.3, 131.8, 130.1, 130, 129.3, 129.2, 128.9, 128.8, 128.2, 128.2, 128.2, 127.3, 126.8, 117.6, 117.4, 113.7, 51.5, 42.3, 32.3, 31.4, 22, 20.7.

Example 157: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a green solid.

¹H NMR (DMSO_(d6)): 11.61 (1H, s), 7.65-7.46 (2H, m), 7.24 (1H, dd, J=10.0, 8.7 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.63-3.52 (6H, m), 3.49 (2H, m), 3.46 (2H, m), 2.78 (1H, dd, J=8.4, 4.3 Hz), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.11 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.8, 160.1, 156, 133, 133, 132.3, 132.3, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.7, 66, 51.6, 51.6, 45.7, 41.7, 32.3, 29, 22.1, 20.7.

Example 158: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a dark yellow solid.

¹H NMR (DMSO_(d6)): 11.60 (1H, s), 7.47-7.40 (2H, m), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.08 (1H, d, J=12.2 Hz), 3.79 (1H, d, J=12.2 Hz), 3.54 (2H, m), 3.44 (4H, m), 2.78 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.58 (2H, m), 1.50 (2H, m), 1.44 (2H, m), 1.10 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 161.2, 159.6, 155.9, 131.6, 130.1, 130.1, 129.3, 129.3, 128.9, 128.7, 128.3, 128.2, 117.6, 117.4, 114, 51.5, 51.5, 46.2, 42.2, 32.3, 29.3, 25.9, 25.2, 23.9, 22.1, 20.7.

Example 159: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a grey powder.

¹H NMR (DMSO_(d6)): 11.80 (1H, s), 8.65 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=9.4, 11.5 Hz), 4.14 (2H, d, J=5.6 Hz), 3.74 (1H, dd, J=11.5, 8.1 Hz), 3.34 (2H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.86 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 168.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.7, 118.6, 118.5, 118.3, 117.5, 113.8, 113.8, 113.6, 113.6, 113.3, 104.1, 104, 103.9, 103.9, 48.6, 35.7, 31, 29.2, 27.2.

Example 160: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, 2 s), 7.80 (1H, 2 d, J=2.1 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.52 (1H, 2 dd, J=4.8 Hz), 4.43 (1H, 2 quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.5 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.37 (1H, m), 3.29-3.18 (4H, m), 2.86 (0.5H, dd, J=8.2, 16.2 Hz), 2.82 (0.5H, dd, J=8.3, 16.0 Hz), 1.83 (1H, m), 1.75 (1H, m), 1.64-1.50 (2H, 2 m), 1.22-1.01 (4H, m).

¹³C NMR (DMSO_(d6)): 167.2, 167.2, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 155, 132.5, 132.4, 129, 129, 118.8, 118.8, 118.7, 118.6, 118.6, 118.5, 114.6, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 71.1, 54.5, 48.5, 35.6, 33.9, 31.8, 31.7, 30.9, 29.4, 29.4, 24.1, 23.7.

Example 161: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a light brown powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.70 (1H, d, J=4.3 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.79 (1H, m), 3.73 (2H, m), 3.22 (2H, s), 3.22 (1H, m), 2.83 (1H, dd, J=15.8, 8.2 Hz), 1.90 (1H, m), 1.76 (1H, m), 1.59 (2H, m), 1.41 (1H, m), 1.30 (1H, m).

¹³C NMR (DMSO_(d6)): 167.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 128.9, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 76, 57.7, 48.5, 35.6, 32.1, 31.5, 29.4, 29.3, 20.4.

Example 162: (S)-N-(2-(1H-pyrazol-1-yl)ethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 8.06 (1H, t, J=5.6 Hz), 7.66 (1H, d, J=2.1 Hz), 7.62 (1H, m), 7.40 (1H, d, J=1.3 Hz), 7.23 (1H, m), 6.17 (1H, t, J=2.1 Hz), 4.42 (1H, quin, J=8.7 Hz), 4.15 (3H, m), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.43 (2H, q, J=6.0 Hz), 3.22 (2H, m), 3.13 (1H, dd, J=15.7, 9.2 Hz), 2.79 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 168, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 155, 154.9, 138.7, 130.1, 129.7, 129.6, 129.2, 118.4, 116.1, 116, 115.9, 115.9, 114, 113.2, 113.2, 113.1, 113.1, 104.9, 50.2, 48.4, 39.8, 35.6, 31.4, 29.1.

Example 163: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an orange solid.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.61 (1H, m), 7.22 (1H, m), 4.58 (0.65H, tt, J=12.3, 3.4 Hz), 4.45 (1H, m), 4.16 (1.35H, m), 3.74 (1H, m), 3.58 (0.7H, m), 3.49 (1.3H, m), 3.43-3.35 (2H, m), 3.22 (1H, m), 3.12 (0.7H, m), 3.04 (1.3H, m), 2.85 (1.95H, s), 2.83 (1H, m), 2.70 (1.05H, s), 2.24-2.07 (2H, m), 1.93 (0.7H, m), 1.79 (1.3H, m).

¹³C NMR (DMSO_(d6)): 167.8, 167.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.1, 155.1, 154.9, 154.8, 129.7, 129.6, 129.5, 129.3, 118.9, 118.8, 118.7, 116.1, 116, 115.9, 115.9, 114.2, 114.1, 113.2, 113.2, 113.1, 113.1, 49.4, 49.3, 49.2, 48.6, 35.7, 35.6, 29.9, 29.4, 29.2, 29.1, 27.7, 27.7, 26.9, 26.6.

Example 164: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.73 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, m), 4.15 (1H, m), 4.06, 3.94 (1H, 2 m), 3.88, 3.83, 3.70-3.61, 3.56, 3.50, 3.38 (4H, several mult.), 3.72 (1H, dd, J=11.4, 8.0 Hz), 3.48, 3.45 (2H, 2 m), 3.22 (1H, dd, J=15.6, 9.4 Hz), 3.07, 3.05 (3H, 2s), 2.84 (1H, m), 2.33 (1H, m), 2.22 (1H, m).

¹³C NMR (DMSO_(d6)): 166.4, 166.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 155.2, 132.5, 132.4, 129.4, 129.4, 118.8, 118.8, 118.7, 118.6, 118.5, 118.5, 113.8, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.6, 60.6, 58.9, 58.9, 48.6, 45.4, 45.4, 45.3, 45.3, 45.1, 44.9, 35.7, 30.3, 30.2, 30.2, 30.2, 29.3, 25.7, 24.1, 24.1.

Example 165: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-8-azaspiro[4.5]decan-8-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.3 Hz), 4.15 (1H, br t, J=10 Hz), 3.73 (3H, m), 3.60-3.27 (8H, m), 3.21 (1H, br dd, J=15.7, 9.2 Hz), 2.80 (1H, br dd, J=15.8, 7.6 Hz), 1.72 (2H, m), 1.47 (2H, m), 1.42 (2H, m).

¹³C NMR (DMSO_(d6)): 166.4, 166.4, 160.8, 159.2, 157.5, 157.5, 155.9, 155.8, 155.1, 132.4, 132.4, 129.1, 118.9, 118.8, 118.7, 114, 114, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 76.9, 76.7, 66.4, 66.4, 48.6, 43.4, 41.6, 36.5, 36.3, 35.6, 34.7, 34, 29.3, 29.2.

Example 166: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1-oxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.68 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.46 (1H, quin, J=8.4 Hz), 4.16 (2H, m), 3.88 (1H, m), 3.82 (1H, m), 3.73 (1H, dd, J=11.3, 8.1 Hz), 3.57 (3H, m), 3.23 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, m), 2.83 (1H, dd, J=15.8, 8.2 Hz), 2.76 (3H, m).

¹³C NMR (DMSO_(d6)): 167, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.4, 118.9, 118.7, 118.6, 113.9, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 45.1, 45, 44.7, 44.6, 37, 37, 37, 35.7, 33.1, 33.1, 29.3, 29.3, 29.2, 28.8, 28.8.

Example 167: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 5.08 (0.6H, m), 4.61 (0.4H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.6, 11.5 Hz), 3.91 (1H, m), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.66 (0.8H, m), 3.63-3.52 (3H, m), 3.48 (1.2H, m), 3.20 (1H, m), 2.88 (1.8H, m), 2.81 (1H, m), 2.72 (1.2H, s), 2.21-2.02 (1H, m), 1.88-1.69 (1H, m).

¹³C NMR (DMSO_(d6)): 168.2, 168.2, 167.7, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 155.1, 132.4, 132.4, 129.3, 129.2, 118.8, 118.7, 118.6, 114.2, 114.2, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 69.3, 69.3, 69.2, 67.1, 67, 56.5, 56.5, 52.9, 48.6, 35.7, 30, 29.8, 29.8, 29.7, 29.7, 29.5, 29.5, 29.3, 29.2, 27.6.

Example 168: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide

To a stirred mixture of 1,3,4-thiadiazol-2-amine (35.2 mg, 0.348 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.06 ml, 0.348 mmol). in dichloromethane (2 mL) was added (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (100 mg, 0.290 mmol) followed by addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.180 ml, 0.290 mmol). The reaction was stirred at room temperature overnight. Thereupon, the organic was removed under vacuum and the residue was purified by column chromatography in a mixture of dichloromethane-methanol. Recrystallization from isopropanol afforded the titled product as an off-white solid. Yield: 76 mg, 61%.

¹H NMR (DMSO_(d6)): 12.72 (1H, s), 11.81 (1H, s), 9.17 (1H, s), 7.61 (1H, m), 7.22 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=9.5, 11.2 Hz), 3.75 (1H, dd, J=11.7, 8.1 Hz), 3.71 (2H, m), 3.26 (1H, dd, J=15.8, 9.2 Hz), 2.88 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 160.2, 160.1, 158.5, 158.5, 158.5, 156.6, 156.5, 155.6, 154.9, 154.9, 148.8, 130.2, 129.7, 129.6, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 112.5, 48.6, 35.6, 31.1, 29.2.

Example 169: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 11.81 (1H, s), 10.61 (1H, s), 8.31 (1H, ddd, J=0.8, 1.8, 4.8 Hz), 8.04 (1H, br d, J=8.2 Hz), 7.77 (1H, m), 7.61 (1H, m), 7.21 (1H, m), 7.10 (1H, ddd, J=7.3, 4.9, 0.9 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.3, 9.4 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.58 (2H, m), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.88 (1H, dd, J=8.3, 15.8 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.4, 154.9, 154.9, 151.9, 148, 138.2, 129.7, 129.6, 119.5, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.6, 113.4, 113.2, 113.2, 113.1, 113.1, 48.6, 35.6, 32.2, 29.2.

Example 170: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide

Compound was prepared analogous manner to Example 168 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.71 (1H, s), 10.62 (1H, s), 8.33 (1H, dd, J=4.7, 1.0 Hz), 8.06 (1H, br d, J=8.1 Hz), 7.79 (1H, m), 7.56 (2H, m), 7.24 (1H, dd, J=10.0, 8.8 Hz), 7.11 (1H, ddd, J=6.7, 5.6, 0.7 Hz), 4.09 (1H, d, J=12.0 Hz), 3.81 (1H, d, J=12.2 Hz), 3.65 (2H, m), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.3, 5.4 Hz), 1.14 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.7, 160.1, 156.1, 151.9, 148, 138.2, 132.9, 132.9, 132.3, 132.3, 129.3, 129.2, 119.5, 118, 117.8, 116.2, 116.2, 113.4, 113.2, 51.6, 32.3, 32.2, 22.2, 20.6.

Example 171: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide

Compound was prepared analogous manner to Example 168 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, br s), 10.33 (1H, br s), 8.75 (1H, br s), 8.27 (1H, d, J=4.1 Hz), 8.04 (1H, d, J=7.9 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.37 (1H, dd, J=8.2, 4.7 Hz), 7.30 (1H, dd, J=9.0, 10.0 Hz), 4.10 (1H, d, J=12.0 Hz), 3.82 (1H, d, J=12.0 Hz), 3.61 (2H, br s), 2.88 (1H, dd, J=8.2, 4.1 Hz), 1.67 (1H, dd, J=8.4, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 161.3, 159.6, 156.2, 144.3, 140.8, 135.7, 132.3, 130.2, 130.1, 129.4, 129.3, 128.9, 128.7, 128.3, 126.3, 123.7, 117.6, 117.4, 113.2, 51.6, 32.4, 32.1, 22.1, 20.7.

Example 172: (R)-1-(2-hydroxyethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 8 from ethyl (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.85 (1H, m), 4.69 (1H, t, J=5.3 Hz), 4.48 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.76 (1H, dd, J=11.6, 8.1 Hz), 3.55 (2H, m), 3.29 (1H, dd, J=15.6, 9.2 Hz), 2.93 (1H, dd, J=15.6, 8.2 Hz), 2.49 (2H, t, J=6.8 Hz).

¹³C NMR (DMSO_(d6)): 155, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 120.4, 120.3, 120.2, 117.6, 105.9, 105.7, 105.5, 59.2, 48.3, 35.8, 29, 28.

Example 173: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 8 from ethyl (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.72 (1H, ddd, J=9.0, 8.0, 5.8 Hz), 7.16 (1Hm), 4.69 (1H, br t, J=5.1 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.13 (1H, dd, J=11.6, 9.1 Hz), 3.71 (1H, dd, J=11.6, 8.1 Hz), 3.54 (2H, m), 3.25 (1H, dd, J=15.6, 9.2 Hz), 2.89 (1H, dd, J=15.6, 8.4 Hz), 2.48 (2H, t, J=6.7 Hz).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.5, 132.4, 128.3, 118.7, 118.6, 118.4, 117.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.2, 48.4, 35.7, 29.1, 28.

Example 174: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 66) and isolated as a beige solid.

¹H NMR (CD₃OD): 7.44 (1H, dd, J=6.4, 2.7 Hz), 7.36 (1H, ddd, J=8.8, 4.4, 2.6 Hz), 7.17 (1H, dd, J=9.8, 8.8 Hz), 4.20 (1H, d, J=12.3 Hz), 3.93 (1H, d, J=12.2 Hz), 3.86 (4H, br), 3.28-3.0 (6H, m), 2.94 (2H, m), 2.85 (1H, dd, J=8.3, 4.0 Hz), 1.71 (1H, dd, J=8.2, 5.6 Hz), 1.18 (1H, dd, J=5.5, 4.2 Hz).

¹³C NMR (CD₃OD): 163.3, 161.6, 157.1, 134.2, 131.5, 131.4, 131, 130.9, 130.7, 130.7, 130, 129.9, 118.6, 118.4, 66.2, 57.3, 54, 53.5, 53.5, 34.2, 23.2, 22.1, 21.3.

Example 175: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(isopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide (Example 67) and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, br s), 8.48 (2H, br s), 7.48 (1H, dd, J=6.5, 2.7 Hz), 7.44 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.31 (1H, dd, J=9.9, 8.9 Hz), 4.08 (1H, d, J=12.2 Hz), 3.80 (1H, d, J=12.0 Hz), 3.31 (1H, m), 3.16 (2H, br t, J=7.5 Hz), 2.97 (1H, dd, J=8.4, 4.3 Hz), 2.80 (2H, m), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.23 (6H, d, J=6.5 Hz), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.2, 159.6, 156.5, 131.7, 130.1, 130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 114.6, 51.5, 51.5, 49.4, 42.3, 32.5, 22.1, 21.4, 20.3, 18.8, 18.8.

Example 176: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 116) and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.0, 9.7 Hz), 3.74-3.68 (2H, m), 3.66 (1H, dd, J=8.6, 5.8 Hz), 3.61 (1H, m), 3.33 (1H, m), 3.31-3.21 (2H, m), 2.88 (1H, dd, J=15.6, 8.2 Hz), 2.67 (2H, m), 2.46 (2H, t, J=7.1 Hz), 1.91 (1H, m), 1.59 (1H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.4, 132.4, 128.1, 118.9, 118.7, 118.6, 118.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.5, 66.3, 57.9, 48.4, 46.3, 35.7, 32.5, 29.2, 25.

Example 177: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 117) and isolated as a white powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.29 (1H, dd, J=15.6, 9.4 Hz), 2.88 (1H, dd, J=15.7, 7.9 Hz), 2.58-2.46 (8H, m), 1.91 (4H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 154.9, 132.4, 132.4, 128.1, 124.4, 122.8, 121.2, 119, 118.9, 118.7, 118, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.9, 49.2, 49.2, 49.1, 48.5, 35.7, 33.5, 33.4, 33.2, 29.2, 22.1.

Example 178: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 130) and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=9.7, 11.1 Hz), 3.71 (1H, dd, J=11.4, 7.9 Hz), 3.27 (1H, dd, J=15.5, 9.2 Hz), 3.08 (2H, m), 2.98 (2H, m), 2.89 (1H, dd, J=15.6, 8.1 Hz), 2.73 (1H, m), 2.68 (2H, t, J=7.2 Hz), 2.46 (2H, t, J=7.1 Hz), 2.01 (2H, m), 1.83 (2H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.1, 118.9, 118.7, 118.6, 118.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.9, 50.4, 48.4, 47.7, 44.8, 35.7, 29.1, 29, 29, 25.

Example 179: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 126) and isolated as a white powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.70 (1H, dd, J=11.7, 7.8 Hz), 3.28 (1H, dd, J=15.6, 9.4 Hz), 3.01 (1H, tt, J=3.6, 12.4 Hz), 3.0-2.94 (2H, m), 2.90 (3H, s), 2.89 (1H, dd, J=8.0, 15.4 Hz), 2.50 (4H, m), 1.94 (4H, m), 1.55 (2H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 154.9, 132.4, 132.4, 128.1, 118.9, 118.8, 118.7, 118.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 58.8, 55.7, 51.4, 51.3, 48.5, 37.4, 35.7, 29.2, 24.4, 24.4, 22.

Example 180: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Example 152) and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.65 (1H, s), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.24 (1H, dd, J=10.2, 8.7 Hz), 4.06 (1H, d, J=11.4 Hz), 3.77 (1H, d, J=12.0 Hz), 3.26 (2H, m), 2.90 (1H, dd, J=8.4, 4.3 Hz), 2.84 (2H, m), 2.54 (2H, m), 1.62 (1H, dd, J=8.3, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 155.8, 132.8, 132.8, 132.3, 132.2, 130.7, 129.5, 129.4, 129, 127.2, 125.3, 123.5, 118, 117.8, 117.5, 116.2, 116.2, 51.4, 49.3, 49.1, 48.9, 48.7, 47.7, 32.2, 24.8, 22.3, 20.4.

Example 181: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(cyclobutylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide (Example 102) and isolated as a white powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, m), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, t, J=8.7 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.26 (1H, dd, J=15.6, 9.4 Hz), 3.18 (1H, quin, J=7.5 Hz), 2.88 (1H, dd, J=15.6, 8.1 Hz), 2.64 (2H, t, J=7.1 Hz), 2.45 (2H, t, J=7.0 Hz), 2.07 (2H, m), 1.75-1.45 (4H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.1, 118.8, 118.7, 118.6, 118, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53.2, 48.4, 44.6, 35.7, 30, 29.1, 24.7, 14.5.

Example 182: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide (Example 118) and isolated as a yellow powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, br s), 7.73 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.5, 11.5 Hz), 3.71 (1H, dd, J=11.5, 8.1 Hz), 3.26 (1H, dd, J=15.5, 9.2 Hz), 3.20 (2H, t, J=6.7 Hz), 2.97 (3H, s), 2.91 (2H, t, J=6.7 Hz), 2.91 (1H, m), 2.70 (2H, t, J=7.0 Hz), 2.47 (2H, t, J=7.0 Hz).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.2, 118.7, 118.6, 118.5, 118, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53.6, 48.4, 47, 42.4, 41.4, 35.7, 29, 24.7.

Example 183: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 131) and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.41 (1H, t, br, J=5.5 Hz), 4.13 (1H, dd, J=11.2, 9.5 Hz), 3.70 (1H, dd, J=11.6, 8.1 Hz), 3.44 (2H, q, J=6.1 Hz), 3.27 (1H, dd, J=15.5, 9.3 Hz), 2.88 (1H, dd, J=15.6, 8.3 Hz), 2.52 (2H, m), 2.48 (2H, t, J=7.1 Hz), 2.41 (2H, t, J=6.2 Hz), 2.18 (3H, s).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.5, 132.4, 127.9, 118.8, 118.6, 118.5, 118.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 58.9, 58.8, 55.8, 48.4, 42, 35.7, 29.1, 22.1.

Example 184: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-1-cyclohexylethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-1-cyclohexylethyl)acetamide (Example 127) and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.84 (1H, br), 7.73 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.13 (1H, dd, J=11.2, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.28 (1H, dd, J=15.7, 9.5 Hz), 2.88 (1H, dd, J=15.6, 8.2 Hz), 2.83, 2.71 (2H, 2 br s), 2.50 (3H, m), 1.68 (2H, br d, J=12.6 Hz), 1.60 (3H, m), 1.38-1.0 (5H, m), 0.94 (4H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 128.2, 118.8, 118.7, 118.6, 113.8, 113.6, 104.1, 103.9, 57, 48.4, 44.8, 41.8, 35.7, 29.2, 29.2, 27.1, 26.2, 26.1, 25.9, 24.6, 15.7.

Example 185: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 70) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, br s), 9.60 (1H, br s), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.8 Hz), 4.08 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=12.2 Hz), 3.39-3.05 (6H, m), 2.97 (1H, dd, J=8.4, 4.3 Hz), 2.83 (2H, m), 1.91 (4H, br s), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 156.5, 132.9, 132.9, 132.4, 132.3, 131.7, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 114.6, 53.4, 52.4, 51.5, 32.4, 22.7, 22.1, 21.3, 20.3.

Example 186: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((cyclopropylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 143) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.79 (1H, s br), 8.39 (2H, s br), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.4, 2.6 Hz), 7.25 (1H, dd, J=9.9, 8.9 Hz), 4.08 (1H, br d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.17 (2H, t, J=7.3 Hz), 2.93 (1H, dd, J=8.2, 4.3 Hz), 2.87-2.73 (4H, m), 1.67 (1H, dd, J=8.1, 5.4 Hz), 1.20 (1H, t, J=4.8 Hz), 1.02 (1H, m), 0.58 (2H, m), 0.34 (2H, m).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 156.5, 133, 132.9, 132.4, 132.3, 131.7, 129.3, 129.2, 118, 117.9, 116.2, 116.2, 114.7, 51.5, 51.4, 44.8, 32.4, 22.1, 21.3, 20.3, 7.3, 3.9, 3.8.

Example 187: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide (Example 154) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.76 (1H, br s), 7.59 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.9 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.14 (2H, m), 2.93 (1H, dd, J=8.3, 4.2 Hz), 2.73 (2H, m), 2.52 (1H, m), 1.65 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.8 Hz), 0.70-0.57 (4H, m).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 156.3, 132.9, 132.9, 132.3, 132.3, 131.4, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 115.4, 51.5, 46.2, 32.4, 29.5, 22.2, 22.2, 20.4, 4.1, 4.

Example 188: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclobutylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide (Example 153) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, s br), 8.44 (1H, s br), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.9 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.65 (1H, quin, J=8.0 Hz), 3.02 (2H, t, J=7.2 Hz), 2.94 (1H, dd, J=8.3, 4.2 Hz), 2.74 (2H, m), 2.18 (2H, m), 2.08 (2H, m), 1.77 (2H, m), 1.66 (1H, dd, J=8.2, 5.3 Hz), 1.20 (1H, t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 156.5, 133, 133, 132.4, 132.3, 131.8, 129.3, 129.2, 118, 117.9, 116.2, 116.2, 114.6, 51.6, 51.6, 51.1, 42.8, 32.4, 26.4, 22.1, 21.6, 20.3, 14.5.

Example 189: (5aS,6aR)-1-(2-(benzylamino)ethyl)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide (Example 156) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.79 (1H, br s), 8.28 (2H, br m), 7.50-7.41 (6H, m), 7.39 (1H, m), 7.31 (1H, dd, J=9.0, 9.9 Hz), 4.10 (2H, s), 4.08 (1H, d, J=12.3 Hz), 3.79 (1H, d, J=12.2 Hz), 3.12 (2H, t, J=6.8 Hz), 2.90 (1H, dd, J=8.4, 4.3 Hz), 2.78 (2H, m), 1.66 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 161.2, 159.6, 156.4, 133.6, 131.5, 130.1, 130.1, 129.5, 129.4, 129.3, 128.9, 128.8, 128.6, 128.6, 128.3, 117.6, 117.4, 115.1, 51.5, 50.6, 45.5, 32.4, 22.1, 21.8, 20.4.

Example 190: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentyl(methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide (Example 155) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.81 (1H, br s), 9.42 (1H, m), 7.63-7.49 (2H, m), 7.25 (1H, t, J=9.3 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.29 (2H, m), 2.95 (2H, dd, J=7.8, 3.9 Hz), 2.78 (4H, br m), 1.97 (2H, br m), 1.78-1.37 (7H, m), 1.17 (1H, m), 1H (br).

¹³C NMR (DMSO_(d6)): 161.7, 160.1, 156.4, 132.9, 132.8, 132.3, 132.3, 131.4, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 66.1, 52.6, 51.5, 37.8, 32.4, 27.9, 23.7, 22.2, 20.3, 19.6.

Example 191: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 157) and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.85 (1H, br s), 11.05 (1H, br s), 7.64-7.52 (2H, m), 7.25 (1H, br t, J=9.3 Hz), 4.08 (1H, d, J=11.9 Hz), 3.98 (2H, br m), 3.79 (3H, m), 3.44 (2H, m), 3.35 (2H, m), 3.10 (2H, br s), 2.97 (3H, br s), 1.67 (1H, m), 1.19 (1H, br s).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 156.6, 132.9, 132.4, 132.3, 131.5, 129.2, 129.1, 118, 117.8, 116.2, 114.3, 63.1, 53.9, 51.5, 51.2, 50.9, 32.4, 22.1, 20.4, 18.7.

Example 192: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyridin-2-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (Example 170) and isolated as a dark beige solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.95 (1H, dd, J=5.4, 1.5 Hz), 7.64-7.43 (3H, m), 7.23 (1H, t, J=9.8 Hz), 6.66 (1H, br s), 6.58 (1H, br s), 4.05 (1H, d, J=11.9 Hz), 3.76 (1H, d, J=12.1 Hz), 3.50 (2H, m), 2.73 (1H, dd, J=8.1, 4.2 Hz), 2.69 (2H, t, J=6.9 Hz), 1.54 (1H, dd, J=8.2, 5.3 Hz), 1.11 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.7, 160.1, 157.3, 155.9, 145.6, 137.9, 132.8, 132.8, 132.2, 132.2, 131.1, 129.4, 129.3, 118, 117.8, 117.1, 116.1, 111.6, 109.2, 51.4, 39.4, 32.2, 24, 22.4, 20.3.

Example 193: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.89 (1H, s), 8.93 (2H, m), 7.63 (1H, m), 7.23 (1H, m), 4.44 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=11.3, 9.4 Hz), 3.75 (1H, dd, J=11.5, 8.4 Hz), 3.31 (1H, dd, J=9.1, 15.6 Hz), 3.09 (2H, br s), 2.94 (1H, dd, J=15.6, 8.7 Hz), 2.76 (2H, m), 2.52 (3H, br s).

¹³C NMR (DMSO_(d6)): 160.2, 160.1, 158.5, 158.5, 156.6, 156.6, 155.9, 155, 154.9, 129.8, 129.7, 129.5, 118.4, 118.2, 118.1, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 48.3, 46.4, 35.8, 32.3, 29, 21.

Example 194: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one (Example 158) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, br s), 9.08 (2H, br s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.44 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.31 (1H, dd, J=9.1, 9.9 Hz), 4.08 (1H, d, J=11.9 Hz), 3.80 (1H, d, J=12.0 Hz), 3.50-2.63 (8H, m), 2.94 (1H, dd, J=8.3, 4.2 Hz), 2.0-1.25 (6H, m), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.18 (1H, t, J=4.5 Hz).

¹³C NMR (DMSO_(d6)): 161.2, 159.6, 156.4, 131.4, 130, 129.4, 129.3, 128.8, 128.7, 128.3, 117.6, 117.4, 114.7, 54.4, 52.6, 51.5, 32.4, 23, 22.1, 21.7, 20.4, 19.6.

Example 195: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 140) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.5, 9.2 Hz), 3.70 (1H, dd, J=11.6, 7.8 Hz), 3.53 (4H, br t, J=4.5 Hz), 3.28 (1H, dd, J=15.6, 9.4 Hz), 2.89 (1H, dd, J=15.6, 8.0 Hz), 2.51 (2H, m) 2.46 (2H, m), 2.34 (4H, br s).

¹³C NMR (DMSO_(d6)): 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 154.8, 132.4, 132.4, 128.1, 119, 118.8, 118.7, 118.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66.2, 56.3, 53, 48.5, 35.7, 29.3, 21.5.

Example 196: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one and isolated as a white solid.

¹H NMR (DMSO_(d6)): 11.93 (1H, s), 11.01 (1H, br s), 7.63 (1Hm), 7.23 (1H, m), 4.47 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.4, 9.2 Hz), 3.96 (2H, br d, J=12.2 Hz), 3.76 (3H, m), 3.40 (2H, br d, J=12.0 Hz), 3.31 (2H, m), 3.05 (2H, m), 2.94 (1H, br dd, J=15.8, 8.1 Hz), 2.89 (2H, br t, J=7.5 Hz).

¹³C NMR (DMSO_(d6)): 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.8, 154.9, 154.9, 129.8, 129.7, 129.1, 118.7, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 63.1, 53.8, 51.1, 48.5, 35.7, 29.1, 18.8.

Example 197: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(pyridin-3-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide (Example 171) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 11.78 (1H, br s), 8.00 (1H, d, J=2.8 Hz), 7.75 (1H, dd, J=4.5, 1.2 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.42 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=9.0, 9.9, Hz), 7.07 (1H, dd, J=8.3, 4.6 Hz), 6.96 (1H, ddd, J=1.2, 2.7, 8.3 Hz), 5.93 (1H, t, J=5.9 Hz), 4.06 (1H, d, J=11.9 Hz), 3.77 (1H, d, J=12.2 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.2, 4.3 Hz), 2.66 (2H, m), 1.56 (1H, dd, J=8.2, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.2, 159.6, 155.9, 144.4, 135.3, 131.1, 130, 129.9, 129.3, 129.2, 129, 128.9, 128.3, 128.2, 123.6, 117.5, 117.4, 117.4, 117, 51.4, 51.4, 41.2, 32.3, 23.9, 22.3, 20.3.

Example 198: (R)-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one (Example 104) and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.92 (1H, s), 10.90 (1H, br s), 7.87 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.5, 9.2 Hz), 3.78 (1H, dd, J=11.6, 7.8 Hz), 3.47 (2H, m), 3.37 (1H, m), 3.32 (2H, m), 2.98 (3H, m), 2.85 (2H, br t, J=7.8 Hz), 1.98 (2H, m), 1.86 (2H, m).

¹³C NMR (DMSO_(d6)): 155.9, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.9, 105.9, 105.8, 105.6, 53, 52, 48.4, 35.8, 29, 22.7, 20.8.

Example 199: (R)-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-1-morpholino-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.95 (1H, s), 11.05 (1H, br s), 7.88 (1H, m), 4.51 (1H, quin, J=8.4 Hz), 4.17 (1H, br dd, J=11.4, 9.4 Hz), 3.96 (2H, br d, J=12.2 Hz), 3.78 (3H, m), 3.41 (2H, m), 3.36 (1H, m), 3.30 (2H, m), 3.06 (2H, m), 2.98 (1H, br dd, J=15.7, 7.9 Hz), 2.89 (2H, m).

¹³C NMR (DMSO_(d6)): 155.9, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.8, 106, 105.8, 105.6, 63.1, 53.8, 51.1, 48.4, 35.8, 29, 18.8.

Example 200: (R)-diethyl 2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate Step 1: tert-butyl (4R)-2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid (2 g, 5.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.68 mL, 9.63 mmol) in dry tetrahydrofuran (20 mL) was added ethyl chloroformate (0.793 mL, 8.26 mmol) at 0-5° C. The mixture was stirred for 4 h in the cold, and then diluted with acetonitrile (10 mL) followed by addition of 2 M (diazomethyl)trimethylsilane (5.51 mL 11.01 mmol) in diethyl ether. The stirring was continued for additional 3 h at 0-5° C. and the mixture was allowed to warm up naturally overnight with stirring under N2. Thereupon, the solvents were removed under vacuum and the residue was purified by column chromatography in a mixture of petroleumether-ethyl acetate. to give (4R)-tert-butyl 2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a yellow oil. Yield: 1.99 g, 93%.

Step 2: tert-butyl (4R)-2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4R)-tert-butyl 2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (1.98 g, 5.11 mmol) in diethyl ether (15 mL) was added 48% HBr (0.61 mL, 5.37 mmol) at 0-5° C. with stirring. After 5 min. the mixture was diluted with ethyl acetate (20 mL) and then washed with sodium bicarbonate solution. The organic phase was dried (MgSO₄), filtered, evaporated to dryness to give (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a yellowish oil. Yield: 1.83 g, 81%.

Step 3: diethyl 2-(2-((4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)-2-oxoethyl)malonate

To a solution of diethyl malonate (0.83 mL, 5.45 mmol) in N,N-dimethyl formamide (7 mL) was added sodium hydride (60% in minar oil) (0.174 g, 4.36 mmol) with ice cooling and the solution was stirred for 30 min. Thereupon, (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (1.6 g, 3.63 mmol) in dry tetrahydrofuran (3.50 mL) was added to the above reaction mixture with ice cooling and the mixture was stirred in the cold for 30 min. The reaction was then diluted with a mixture of ethyl acetate-petroleumether (2:1), washed with NaHSO₄ solution (40 mL), dried over MgSO₄, filtered and evaporated to dryness. Chromatography in a mixture of ethyl acetate-petroleumether afforded the titled product as a white powder. Yield: 1.15 g, 60%.

Step 4: diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate hydrochloride

Diethyl 2-(2-((4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)-2-oxoethyl)malonate (1.3 g, 2.502 mmol) was dissolved in 4 M HCl (9.38 mL, 37.5 mmol) in dioxane and the solution was stirred for 2 h. Thereupon, the mixture was diluted with diethyl ether (ca. 150 mL) The resulting crystals were collected, washed with diethyl ether and dried under vacuum at 50° C. to give diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate hydrochloride as a white powder. Yield: 1.02 g, 89%.

Step 5: diethyl (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate

A mixture of diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate hydrochloride (1.01 g, 2.216 mmol), potassium isothiocyanate (0.237 g, 2.437 mmol) and cc. HCl (0.092 mL, 1.108 mmol) in abs. ethanol (22 mL) was stirred under reflux for 30 min. The suspension was then cooled to room temperature, evaporated to dryness and the residue was partitioned between dichloromethane and water. The organic phase was dried (MgSO₄), filtered and evaporated to dryness to give the titled product as a yellow powder. Yield: 0.94 g, 92% yield.

¹H NMR (DMSO_(d6)): 1.80 (1H, s), 7.85 (1H, m), 4.47 (1H, quin, J=8.4 Hz), 4.20-4.05 (5H, m), 3.81 (1H, t, J=8.0 Hz), 3.74 (1H, dd, J=11.8, 7.4 Hz), 3.28 (1H, dd, J=15.8, 9.4 Hz), 2.93-2.80 (3H, m), 1.14 (6H, q, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 168, 167.9, 155.7, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 129.1, 120.6, 120.5, 120.4, 115.6, 105.9, 105.7, 105.6, 61.3, 61.2, 50.1, 48.5, 35.7, 29, 23.5, 13.8, 13.8.

Example 201: (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid

To a solution of (R)-diethyl 2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate (Example 200) (0.9 g, 1.955 mmol) in methanol (20 mL) was added 1 M sodium hydroxide solution (11.72 mL, 11.72 mmol) and the mixture was stirred at room temperature overnight. Thereupon, methanol was removed by vacuum, the residue was diluted with water (20 mL) and then acidified to pH=1 by addition of 2 M HCl solution with ice cooling. The mixture was then extracted with 50 mL of mixture of dichloromethane-isopropanol (9:1), the organic phase was dried over MgSO₄, filtered and evaporated to 5 mL volume. The resulting precipitate was collected by filtration washed with petroleum ether and dried under vacuum at 50° C. to give (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid as a yellow powder. Yield: 0.74 g, 94%.

¹H NMR (DMSO_(d6)): 12.93 (1H, br s), 11.79 (1H, s), 7.85 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.6, 9.2 Hz), 3.75 (1H, dd, J=8.0, 11.5 Hz), 3.56 (1H, t, J=8.0 Hz), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.89 (1H, dd, J=15.8, 8.2 Hz), 2.80 (2H, dd, J=7.9, 2.9 Hz).

¹³C NMR (DMSO_(d6)): 169.8, 169.8, 155.5, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.6, 128.8, 120.3, 120.2, 120.1, 116.4, 105.9, 105.8, 105.6, 50.6, 48.3, 35.7, 29, 23.7.

Example 202: (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid

To a solution of (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid (0.1 g, 0.247 mmol) in formic acid (0.237 mL, 6.18 mmol) was added triethylamine (0.345 mL, 2.473 mmol) dropwise with stirring (exothermic reaction), and then the resulting solution was stirred at 115° C. for 1 h. Thereupon, the mixture was diluted with water to 4 mL, the resulting oily mixture treated with 2 M HCl (0.5 mL) and then aged for 30 min. The resultant solid was collected washed with water and dried under vacuum at 50° C. to give (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid as a beige powder. Yield: 0.051 g, 57%.

¹H NMR (DMSO_(d6)): 12.22 (1H, br), 11.78 (1H, s), 7.85 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.7, 9.2 Hz), 3.75 (1H, dd, J=11.7, 7.8 Hz), 3.30 (1H, br dd, J=15.7, 9.4 Hz), 2.92 (1H, dd, J=15.7, 8.1 Hz), 2.63-2.54 (2H, m), 2.5 (2H, m).

¹³C NMR (DMSO_(d6)): 173.4, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128, 127.7, 120.4, 120.3, 120.2, 118.7, 105.9, 105.7, 105.6, 48.3, 35.8, 32.2, 29, 19.7.

Example 203: (R)-N-(cyclopropylmethyl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 7.90 (1H, br t, J=5.5 Hz), 7.86 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.29 (1H, dd, J=15.7, 9.2 Hz), 2.91 (1H, m), 2.89 (2H, br t, J=6.2 Hz), 2.57 (2H, m), 2.34 (2H, t, J=7.4 Hz), 0.83 (1H, m), 0.35 (2H, m), 0.09 (2H, m).

¹³C NMR (DMSO_(d6)): 170.5, 155, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.5, 127.5, 120.5, 120.4, 120.3, 119.1, 105.9, 105.7, 105.5, 48.2, 42.8, 35.8, 33.4, 29.1, 20, 10.7, 3.1.

Example 204: (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, br s), 7.85 (1H, t, J=9.0 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.36 (2H, t, J=6.8 Hz), 3.30 (1H, br dd, J=15.7, 9.4 Hz), 3.25 (2H, t, J=6.9 Hz), 2.93 (1H, dd, J=15.7, 8.1 Hz), 2.56 (2H, m), 2.51 (2H, m), 1.84 (2H, m), 1.74 (2H, m).

¹³C NMR (DMSO_(d6)): 169, 155, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.6, 120.5, 120.4, 120.3, 119.2, 105.8, 105.7, 105.5, 48.2, 45.7, 45.3, 35.8, 32.2, 28.9, 25.5, 23.9, 19.5.

Example 205: (R)-1-morpholino-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, br s), 7.86 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.52 (4H, dt, J=13.2, 4.7 Hz), 3.42 (4H, m), 3.31 (1H, dd, J=9.3, 15.7 Hz), 2.94 (1H, dd, J=15.6, 8.1 Hz), 2.58 (4H, m).

¹³C NMR (DMSO_(d6)): 169.6, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.6, 120.4, 120.3, 120.2, 119.1, 105.9, 105.7, 105.5, 66.1, 66.1, 48.2, 45.2, 41.5, 35.8, 30.5, 28.9, 19.8.

Example 206: (R)-1-(4,4-difluoropiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a light yellow powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.86 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.5, 9.3 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.54 (4H, m), 3.31 (1H, m), 2.94 (1H, dd, J=15.7, 8.2 Hz), 2.66 (2H, m), 2.57 (2H, m), 1.98 (2H, m), 1.88 (2H, m).

¹³C NMR (DMSO_(d6)): 169.5, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 143.7, 143.6, 127.6, 124.3, 122.7, 121.1, 120.4, 120.3, 120.2, 119, 105.9, 105.7, 105.6, 48.2, 41.6, 41.5, 41.5, 38.1, 38, 38, 35.8, 34, 33.8, 33.7, 33.3, 33.2, 33, 30.5, 28.9, 19.9.

Example 207: (R)-1-(piperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.72 (1H, br s), 7.86 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.6, 9.2 Hz), 3.75 (1H, dd, J=11.7, 7.8 Hz), 3.37 (4H, m), 3.30 (1H, dd, J=9.3, 11.8 Hz), 2.93 (1H, dd, J=15.6, 8.1 Hz), 2.57 (4H, m), 1.55 (2H, m), 1.45 (2H, m), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 168.9, 155, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.6, 143.6, 127.6, 120.4, 120.3, 120.2, 119.2, 105.8, 105.7, 105.5, 48.2, 45.7, 41.9, 35.8, 30.7, 28.9, 26, 25.3, 24, 20.

Example 208: (R)-1-(4-methylpiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.73 (1H, s), 7.86 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.32 (1H, br d, J=13.2 Hz), 4.14 (1H, m), 3.81 (1H, br d, J=13.5 Hz), 3.74 (1H, dd, J=11.7, 8.0 Hz), 3.30 (1H, m), 2.92 (2H, br dd, J=15.1, 8.8 Hz), 2.56 (4H, m), 2.47 (1H, m), 1.57 (3H, m), 0.95 (1H, m), 0.87 (4H, m).

¹³C NMR (DMSO_(d6)): 168.9, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 127.5, 120.4, 120.4, 120.3, 120.3, 120.2, 120.2, 119.2, 119.2, 105.9, 105.7, 105.6, 48.2, 45, 44.9, 41.3, 35.8, 34.2, 33.5, 30.7, 30.6, 30.3, 29, 29, 21.6, 20.

Example 209: (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride Step 1: tert-butyl (4R)-2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate hydrobromide

To a solution of (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 200 step 2) (0.1 g, 0.227 mmol) in dry tetrahydrofuran (1 mL) was added morpholine (0.020 mL, 0.227 mmol) at room temperature in one portion. The reaction was stirred for 15 min. and then diluted with diethyl ether (1 mL). The resulting solid was filtered off and the filtrate was evaporated to dryness to give (4R)-tert-butyl 2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate hydrobromide as viscous oil. Yield: 0.105 g, 88%.

Step 2: 2-morpholino-1-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethan-1-one dihydrochloride

(4R)-tert-butyl 2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate hydrobromide (0.105 g, 0.199 mmol) was dissolved in 4 M HCl (0.996 mL, 3.98 mmol) in dioxane and the solution was stirred for 1 h. Thereupon, the mixture was diluted with diethyl ether (ca. 10 mL) an the resulting precipitate was aged for 30 min with stirring. The solid was collected, washed with diethyl ether and dried to give 2-morpholino-1-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone dihydrochloride as a white powder. Yield: 0.083 g, 99%.

Step 3: (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

A mixture of 2-morpholino-1-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone dihydrochloride (0.078 g, 0.186 mmol), potassium isothiocyanate (0.027 g, 0.279 mmol) and cc. HCl (0.022 mL, 0.130 mmol) in a mixture of ethanol (1 mL) and water (1 mL) was stirred under reflux for 30 min. Thereupon, the mixture was diluted with water (ca. 2 mL) and then ethanol was removed under vacuum. The aqueous residue was neutralized by addition of sodium bicarbonate solution and then extracted with dichloromethane. The organic phase was dried (MgSO₄), filtered and evaporated to dryness. The oily residue was taken up in isopropanol (ca. 1 mL), acidified by addition of 2 M HCl in diethyl ether, and then diluted with diethyl ether to 10 mL. The resulting precipitate was collected, washed with diethyl ether and dried in vacuum at 50° C. to give (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride as an off-white powder, Yield: 0.050 g, 63%.

¹H NMR (DMSO_(d6)): 12.07 (1H, s), 11.58 (1H, br s), 7.88 (1H, m), 4.54 (1H, quin, J=8.5 Hz), 4.23 (1H, dd, J=11.7, 9.2 Hz), 4.15 (2H, m), 3.97 (2H, br d, J=12.5 Hz), 3.85 (1H, dd, J=11.7, 7.8 Hz), 3.78 (2H, br t, J=12.0 Hz), 3.52 (1H, dd, J=9.4, 16.3 Hz), 3.29 (2H, br dd, J=18.0, 13.4 Hz), 3.12 (1H, dd, J=16.4, 8.1 Hz), 3.04 (2H, m).

¹³C NMR (DMSO_(d6)): 157.4, 146.4, 146.4, 146.3, 145.3, 145.2, 144.8, 144.7, 144.7, 143.7, 143.6, 135.6, 120, 108.2, 106, 105.9, 105.7, 63.1, 50.2, 48.9, 48.5, 35.6, 29.6.

Example 210: (R)-1-(pyrrolidin-1-ylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 209 and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.11 (1H, s), 11.13 (1H, br s), 7.87 (1H, m), 4.53 (1H, quin, J=8.4 Hz), 4.23 (1H, dd, J=11.4, 9.4 Hz), 4.15 (2H, br s), 3.84 (1H, dd, J=11.7, 7.6 Hz), 3.52 (1H, br dd, J=16.2, 9.3 Hz), 3.38 (2H, m), 3.12 (1H, br dd, J=16.3, 7.8 Hz), 3.03 (2H, br s), 1.99 (2H, br s), 1.88 (2H, br s).

¹³C NMR (DMSO_(d6)): 157, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 134.1, 120.3, 120.2, 111.1, 106, 105.8, 105.7, 52.2, 48.9, 46.1, 35.6, 29.5, 22.7.

Example 211: (R)-1-(((2-hydroxyethyl)(methyl)amino)methyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 209 and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 12.10 (1H, br s), 10.45 (1H, br s), 7.88 (1H, br s), 5.35 (1H, br), 4.55 (1H, m), 4.23 (1H, dd, J=11.5, 9.3 Hz), 4.17 (2H, m), 3.85 (1H, m), 3.77 (2H, br t, J=5.2 Hz), 3.49 (1H, dt, J=9.9, 16.3 Hz), 3.19 (1H, m), 3.09 (1H, m), 3.04 (1H, m), 2.81 (0.5H, br s), 2.72 (2.5H, br t, J=5.6 Hz).

¹³C NMR (DMSO_(d6)): 157.4, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 135.6, 120.2, 120.1, 120.1, 108.5, 108.5, 106, 105.8, 105.7, 56, 56, 55.2, 48.9, 48.6, 48.6, 42.4, 39, 35.6, 35.6, 29.6.

Example 212: (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Step 1: tert-butyl (4R)-2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of dimethyl methylphosphonate (0.655 mL, 6.04 mmol) in dry tetrahydrofuran (12 mL) was added N-butyllithium (4.15 mL, 6.65 mmol) (1.6 M in hexane) at −78° C., and the mixture was stirred for 30 min in the cold. Thereupon, a solution of (4R)-1-tert-butyl 2-methyl 4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1,2-dicarboxylate (1.14 g, 3.02 mmol) in tetrahydrofuran (12 mL) was added, and the reaction mixture was stirred for 2 h in the cold. The reaction mixture was quenched with saturated ammonium chloride solution and then extracted with ethyl acetate (20 mL). The organic phase was dried over MgSO₄, filtered and evaporated to leave a colorless oil which was purified by column chromatography in a mixture of petroleumether-ethyl acetate to give (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a colorless oil. (Yield: 0.86 g, 60% yield).

Step 2: tert-butyl (4R)-2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.2 g, 0.426 mmol) in ethanol (2.5 mL) was added potassium carbonate (0.065 g, 0.469 mmol) and the mixture was stirred at room temperature for 15 min. Thereupon, 3-pyridinecarboxaldehyde (0.044 mL, 0.469 mmol) was added and the stirring was continued for 2 h. The resulting solid was filtered off, the filtrate was evaporated to dryness, and then purified by column chromatography in a mixture of petroleumether-ethyl acetate to give (4R)-tert-butyl 2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as an oil. Yield: 0.19 g, 99%.

Step 3: tert-butyl (4R)-2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

A solution of (4R)-tert-butyl 2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.18 g, 0.400 mmol) in ethyl acetate (5 mL) was hydrogenated over 10% palladium on charcoal (0.043 g, 0.040 mmol) for 7 h with a H₂ balloon. Thereupon, the catalyst was filtered through a celite pad and the filtrate was evaporated to give (4R)-tert-butyl 2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as an oil. Yield: 0.16 g, 88%.

Step 4: (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

(4R)-tert-butyl 2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.16 g, 0.354 mmol) was dissolved in 4 M HCl (1.33 mL, 5.30 mmol) in dioxane and the solution was stirred for 1 h. The mixture was then diluted with diethyl ether ether (ca. 10 mL) to give a semi-solid precipitate. Thereupon, diethyl ether was decanted and the residue was dissolved in mixture of ethanol (2 mL) and water (2 mL) followed by addition of 6 M HCl (0.03 mL, 0.177 mmol) and potassium isothiocyanate (0.052 g, 0.530 mmol). The mixture was stirred under reflux for 30 min. After being cooled to room temperature, the pH was set to 7-8 by addition of 1 M sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane, the organic phase was dried (MgSO₄), filtered and evaporated to dryness. The residue was purified by chromatography in a mixture of dichloromethane-methanol to give (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white powder. Yield: 0.049 g, 35%.

¹H NMR (DMSO_(d6)): 11.87 (1H, s), 8.38 (2H, m), 7.84 (1H, m), 7.57 (1H, dt, J=7.8, 2.0 Hz), 7.28 (1H, dd, J=7.8, 4.8 Hz), 4.40 (1H, quin, J=8.4 Hz), 4.12 (1H, dd, J=11.6, 9.1 Hz), 3.73 (1H, dd, J=11.7, 7.6 Hz), 3.08 (1H, dd, J=15.6, 9.2 Hz), 2.85 (2H, m), 2.67 (2H, t, J=7.7 Hz), 2.65 (1H, m).

¹³C NMR (DMSO_(d6)): 155.3, 149.6, 147.3, 146.4, 146.4, 146.3, 146.2, 146.2, 145.3, 145.2, 145.2, 145.2, 145.1, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 136.1, 135.8, 127.9, 123.3, 120.4, 120.3, 120.2, 118.6, 105.8, 105.7, 105.5, 48.2, 35.8, 30.8, 28.8, 25.4.

Example 213: (R)-1-(2-(pyridin-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 11.85 (1H, s), 8.45 (1H, m), 7.84 (1H, m), 7.66 (1H, td, J=7.6, 1.9 Hz), 7.20 (1H, d, J=7.8 Hz), 7.17 (1H, ddd, J=7.4, 4.9, 1.0 Hz), 4.39 (1H, quin, J=8.4 Hz), 4.11 (1H, dd, J=11.6, 9.1 Hz), 3.71 (1H, dd, J=11.7, 7.6 Hz), 3.11 (1H, dd, J=15.6, 9.3 Hz), 2.98 (2H, m), 2.78 (2H, m), 2.66 (1H, dd, J=15.6, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 159.9, 155.1, 148.9, 146.4, 146.3, 146.2, 145.2, 145.1, 145.1, 145.1, 145.1, 144.8, 144.7, 144.7, 144.6, 144.6, 144.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 136.4, 127.7, 122.8, 121.4, 120.5, 120.4, 120.3, 119, 105.8, 105.7, 105.5, 48.2, 35.8, 35.7, 28.9, 23.6.

Example 214: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.86 (1H, s), 8.39 (2H, m), 7.71 (1H, ddd, J=5.9, 8.1, 8.7 Hz), 7.57 (1H, dt, J=7.9, 2.0 Hz), 7.28 (1H, ddd, J=7.8, 4.8, 0.8 Hz), 7.15 (1H, m), 4.36 (1H, m), 4.10 (1H, m), 3.67 (1H, dd, J=11.6, 7.8 Hz), 3.04 (1H, dd, J=15.6, 9.2 Hz), 2.85 (2H, m), 2.67 (2H, t, J=7.7 Hz), 2.61 (1H, dd, J=15.6, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 160.7, 160.7, 159.1, 159, 157.5, 157.4, 155.9, 155.8, 155.2, 149.6, 147.3, 136.1, 135.8, 132.4, 132.4, 128.1, 123.3, 118.7, 118.6, 118.5, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.4, 35.7, 30.8, 28.9, 25.4.

Example 215: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 212 and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.86 (1H, s), 8.64 (2H, m), 8.09 (1H, br d, J=7.8 Hz), 7.73 (1H, dd, J=7.7, 5.5 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.38 (1H, quin, J=8.5 Hz), 4.11 (1H, dd, J=11.2, 9.4 Hz), 3.68 (1H, dd, J=11.6, 7.6 Hz), 3.11 (1H, br dd, J=15.6, 9.3 Hz), 2.99 (2H, m), 2.73 (2H, t, J=7.5 Hz), 2.67 (1H, dd, J=15.7, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 160.1, 160, 158.4, 158.4, 156.5, 156.4, 155.3, 154.9, 154.8, 144.5, 142.7, 142, 138.8, 129.7, 129.6, 128.3, 125.5, 118.9, 118.8, 118.6, 118, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 48.4, 35.6, 30.5, 28.9, 24.9.

Example 216: (R)-1-(3-ethoxypropyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a white powder.

¹H NMR (DMSO_(d6)): 11.77 (1H, s), 7.85 (1H, m), 4.50 (1H, quin, J=8.4 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.76 (1H, dd, J=11.7, 7.6 Hz), 3.36 (2H, m), 3.31 (3H, m), 2.90 (1H, dd, J=15.7, 7.8 Hz), 2.38 (2H, t, J=7.5 Hz), 1.73 (2H, quin, J=6.9 Hz), 1.07 (3H, t, J=7.0 Hz).

¹³C NMR (DMSO_(d6)): 155.1, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 127.5, 120.6, 120.5, 120.4, 119.2, 105.8, 105.7, 105.5, 68.5, 65.2, 48.3, 35.8, 28.9, 27.7, 20.8, 15.1.

Example 217: (R)-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.89 (1H, br s), 7.85 (1H, m), 6.99 (1H, s), 6.72 (1H, s), 4.43 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=9.4, 11.3 Hz), 3.75 (1H, br dd, J=11.5, 8.0 Hz), 3.51 (3H, s), 3.18 (1H, br dd, J=15.6, 9.4 Hz), 2.85 (2H, dd, J=7.1, 8.8 Hz), 2.79 (1H, br dd, J=15.6, 8.1 Hz), 2.73 (2H, dd, J=7.1, 8.8 Hz).

¹³C NMR (DMSO_(d6)): 155.1, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.5, 127.9, 126.1, 121, 120.3, 119, 105.9, 105.7, 105.6, 48.2, 35.8, 32, 28.7, 24.9, 22.2.

Example 218: (R)-1-(2-(pyridin-4-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a light yellow powder.

¹H NMR (DMSO_(d6)): 11.87 (1H, s), 8.43 (2H, m), 7.84 (1H, m), 7.19 (2H, m), 4.41 (1H, quin, J=8.4 Hz), 4.13 (1H, dd, J=11.6, 9.1 Hz), 3.73 (1H, dd, J=11.7, 7.5 Hz), 3.13 (1H, dd, J=15.7, 9.4 Hz), 2.85 (2H, m), 2.68 (3H, m).

¹³C NMR (DMSO_(d6)): 155.3, 149.6, 149.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.2, 145.2, 145.2, 145.2, 145.1, 145.1, 145.1, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 127.9, 123.8, 120.5, 120.4, 120.3, 118.5, 105.9, 105.7, 105.6, 48.3, 35.8, 32.8, 28.9, 24.6.

Example 219: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one (Example 204) and isolated as a yellowish powder.

¹H NMR (DMSO_(d6)): 11.86 (1H, br s), 10.76 (1H, br s), 7.87 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.4, 9.3 Hz), 3.77 (1H, br dd, J=11.6, 7.8 Hz), 3.49 (2H, m), 3.34 (1H, dd, J=6.4, 11.7 Hz), 3.05 (2H, m), 2.96 (1H, dd, J=8.0, 15.8 Hz), 2.93 (2H, m), 2.46 (2H, br t, J=7.4 Hz), 1.95 (4H, m), 1.87 (2H, m).

¹³C NMR (DMSO_(d6)): 155.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 128, 120.4, 120.3, 120.2, 118.2, 105.9, 105.7, 105.6, 53, 52.8, 48.3, 35.8, 28.9, 23.9, 22.6, 21.3.

Example 220: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide Step 1: (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

To a stirred solution of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (1 g, 2.90 mmol) in a mixture of Toluene (20 mL) and ethanol (0.85 mL, 14.50 mmol) was added triethylamine (0.48 mL, 3.48 mmol) followed by dropwise addition of diphenyl phosphorazidate (0.75 mL 3.48 mmol) at room temperature.

The reaction mixture was heated at reflux for 3 h. The solvent was then removed under reduced pressure and the obtained crude oil was purified by column chromatography in a mixture of dichloromethane-methanol. The obtained oil was dissolved in 2 mL of methanol and treated with 2 mL of 1 M potassium hydroxide solution and the reaction was stirred at room temperature overnight. Thereupon, the mixture was diluted with water and extracted with a mixture of dichloromethane:isopropanol (7:3). The organic phase was evaporated to dryness and the product was purified by chromatography. Yield: 74 mg, 8%.

Step 2: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide

To a stirred solution of (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione (70 mg, 0.222 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.042 mL, 0.244 mmol) was added cyclopropanecarbonyl chloride (0.024 mL, 0.266 mmol) and the reaction was stirred for 1 h at room temperature. The reaction was then diluted with 10 mL of dichloromethane, washed with 1 M HCl and concentrated NaHCO₃, respectively. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The residue was dissolved in 2 mL of 4 N HCl in dioxane and stirred overnight at room temperature. Thereupon, the solvent was removed under vacuum and the crude product was purified by column chromatography in a mixture of dichloromethane-methanol. Trituration in diethyl ether afforded (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide as an off-white solid. Yield: 16 mg, 18%.

¹H NMR (DMSO_(d6)): 11.81 (1H, br s), 8.40 (1H, t, J=5.4 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.5, 9.2 Hz), 4.02 (2H, m), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.87 (1H, dd, J=15.8, 8.1 Hz), 1.55 (1H, m), 0.64 (4H, m).

¹³C NMR (DMSO_(d6)): 172.7, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.5, 154.9, 154.9, 129.7, 129.7, 128.9, 118.8, 118.7, 118.6, 117.5, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 48.5, 35.6, 33.2, 29.2, 13.4, 6.3, 6.3.

Example 221: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide Step 1: (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

To a stirred solution of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (1 g, 2.90 mmol) in 1,4-Dioxane (100 ml) was added in triethylamine (0.404 ml, 2.90 mmol) followed by addition of diphenyl phosphorazidate (0.686 ml, 3.19 mmol) and the reaction was stirred at room temperature for 30 min. The above mixture was added dropwise to a pre-heated (80° C.) solution of formic acid (0.657 mL, 17.40 mmol) and hydrogen chloride (5.80 mL, 5.80 mmol) in 1,4-Dioxane (100 mL). The reaction was stirred in the warm 90 min. and then cooled to room temperature. The solvent was removed under vacuum and the residue was azeotroped with isopropanol. Recrystallization from a mixture of isopropanol-diethyl ether afforded yield (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride. Yield: 395 mg, 38%.

Step 2: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopentanecarboxamide

To a stirred solution of (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (75 mg, 0.213 mmol) in dichloromethane (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.076 mL, 0.426 mmol). After being stirred for 15 min. at room temperature, cyclopentanecarboxylic acid (36.5 mg, 0.319 mmol) was added followed by addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.198 ml, 0.319 mmol). The reaction was stirred overnight at room temperature. Thereupon, the mixture was diluted with 10 mL of dichloromethane, washed with 1 M HCl, saturated NaHCO₃ and brine, respectively. The organics were dried over MgSO₄, filtered and evaporated to dryness. Chromatography in a mixture of dichloromethane-isopropanol afforded (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopentanecarboxamide as an off-white solid. Yield: 31 mg, 35%.

¹H NMR (DMSO_(d6)): 11.79 (1H, s), 8.11 (1H, t, J=5.5 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=11.3, 9.4 Hz), 4.01 (2H, m), 3.71 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 2.50 (1H, m), 1.70 (2H, m), 1.58 (4H, m), 1.47 (2H, m).

¹³C NMR (DMSO_(d6)): 175.4, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 128.7, 118.9, 118.7, 118.6, 117.7, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 48.5, 44.1, 35.6, 33, 29.9, 29.9, 29.3, 25.6.

Example 222: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

Compound was prepared analogous manner to Example 221 from (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.80 (1H, br s), 8.14 (1H, br t, J=5.4 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.5, 9.3 Hz), 4.02 (2H, m), 3.83 (2H, m), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.25 (3H, m), 2.85 (1H, dd, J=15.8, 8.1 Hz), 2.35 (1H, m), 1.54 (4H, m).

¹³C NMR (DMSO_(d6)): 174, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 128.7, 118.9, 118.8, 118.6, 117.5, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 66.4, 48.5, 40.6, 35.6, 33, 29.2, 28.8.

Example 223: (S)-N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)nicotinamide

Compound was prepared analogous manner to Example 221 from (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.90 (1H, br s), 9.03 (1H, t, J=5.4 Hz), 9.00 (1H, dd, J=2.3, 0.8 Hz), 8.70 (1H, dd, J=4.8, 1.7 Hz), 8.18 (1H, dt, J=8.1, 1.9 Hz), 7.60 (1H, m), 7.50 (1H, ddd, J=7.9, 4.8, 0.7 Hz), 7.20 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.27 (2H, m), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.7, 7.9 Hz), 3.26 (1H, dd, J=15.8, 9.4 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 165, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.6, 154.9, 154.9, 152, 148.4, 135, 129.7, 129.6, 129.5, 129, 123.5, 118.7, 118.6, 118.5, 117, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 33.7, 29.2.

Example 224: 2-{[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl]methyl}-1-cyanoguanidine

To a stirred suspension of (S)-1-(aminomethyl)-6-(3-bromo-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (prepared analogous manner to Example 221 step 1) (0.23 g, 0.580 mmol) in tetrahydrofuran (29.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.203 mL, 1.160 mmol), followed by quick addition of diphenyl N-cyanocarbonimidate (0.276 g, 1.160 mmol), and then the reaction was stirred for 30 min. at room temperature. Thereupon, 7 M ammonia in methanol (4.14 mL, 29.0 mmol) was added and the mixture was heated at 80° C. overnight in a sealed tube. Thereupon, the reaction was cooled to room temperature and evaporated to dryness under reduced pressure. Chromatography in a mixture of dichloromethane-methanol afforded the product as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.83 (1H, s), 7.73 (1H, m), 7.17 (1H, m), 6.97 (1H, s br), 6.81 (2H, s br), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, m), 4.03 (2H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.25 (1H, dd, J=9.4, 15.7 Hz), 2.86 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 161.1, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.7, 132.5, 132.4, 129.2, 118.8, 118.6, 118.5, 117.8, 116.9, 113.8, 113.8, 113.6, 113.6, 104.1, 103.9, 48.5, 35.6, 35, 29.3.

Example 225: (S,Z)-N-((6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)-N′-cyanopyrrolidine-1-carboximidamide

Compound was prepared analogous manner to Example 224 and isolated as a dark yellow solid.

¹H NMR (DMSO_(d6)):11.74 (1H, s), 7.73 (1H, m), 7.17 (1H, m), 7.04 (0.8H, t, J=5.6 Hz), 6.87 (0.2H, s), 4.45 (1H, quin, J=8.7 Hz), 4.24-4.09 (2.6H, m), 3.98 (0.4H, t, J=6.1 Hz), 3.71 (1H, dd, J=11.7, 8.0 Hz), 3.47 (3.2H, br s), 3.30-3.16 (1.8H, m), 2.90 (1H, m), 1.84, 1.77 (4H, m).

¹³C NMR (DMSO_(d6)):160.8, 160.8, 159.2, 159.1, 158.6, 157.5, 157.5, 156.3, 155.9, 155.9, 155.6, 155.5, 132.5, 132.4, 129, 119.1, 118.7, 118.6, 118.6, 118.5, 118.3, 117.4, 117.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 47.8, 36.2, 35.6, 29.2, 24.8.

Example 226: (S)-N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylnicotinamide

Compound was prepared analogous manner to Example 168 from (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (Example 193) and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.93 (0.5H, br s), 11.64 (0.5H, br s), 8.63 (0.5H, br d, J=4.0 Hz), 8.59 (0.5H, br d, J=4.0 Hz), 8.57 (0.5H, br s), 8.43 (0.5H, s), 7.78 (05H, br d, J=7.6 Hz), 7.62 (1H, m), 7.51 (0.5H, br d, J=7.6 Hz), 7.45 (0.5H, br dd, J=7.0, 5.3 Hz), 7.42 (0.5H, m), 7.21 (1H, m), 4.46 (0.5H, m), 4.37 (0.5H, quin, J=8.5 Hz), 4.15 (1H, m), 3.73 (1H, m), 3.65 (1H, m), 3.41 (1H, m), 3.31 (0.5H, m), 3.01 (0.5H, dd, J=9.2, 15.8 Hz), 2.97 (1.5H, s), 2.91 (1H, dd, J=7.9, 15.6 Hz), 2.87 (1.5H, s), 2.70 (1H, m), 2.53 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.8, 160.1, 160.1, 158.5, 158.4, 156.5, 156.5, 155.5, 155.5, 155.4, 154.9, 154.8, 150.3, 150, 147.5, 146.9, 134.5, 134.2, 132.2, 132.1, 129.7, 129.7, 129.6, 128.9, 128.8, 128.7, 123.5, 123.4, 118.8, 118.7, 118.6, 118.5, 118.4, 118.3, 116.9, 116.1, 116.1, 116, 115.9, 115.9, 113.2, 113.1, 49.9, 48.5, 48.3, 45.9, 37.3, 35.7, 32.5, 28.9, 28.6, 22.7, 21.9.

Example 227: (S)-N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide

To a stirred suspension of (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (Example 193) (87 mg, 0.229 mmol in pyridine (2 mL) was added pyrrolidine-1-carbonyl chloride (0.030 mL, 0.275 mmol) an the reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane (10 mL) and washed three times with 5 mL of 1 M HCl. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The crude product was purified by chromatography in a mixture of dichloromethane-methanol. Crystallization from ethyl acetate afforded (S)-N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide as a white solid. Yield: 23 mg, 22%.

¹H NMR (DMSO_(d6)): 11.82 (1H, s), 7.62 (1H, m), 7.22 (1H, m), 4.42 (1H, quin, J=8.7 Hz), 4.12 (1H, dd, J=9.5, 11.2 Hz), 3.72 (1H, dd, J=11.5, 8.1 Hz), 3.30 (2H, t, J=7.0 Hz), 3.24 (1H, dd, J=15.6, 9.2 Hz), 3.16 (4H, m), 2.86 (1H, dd, J=15.6, 8.4 Hz), 2.71 (3H, s), 2.56 (2H, br t, J=7.0 Hz), 1.71 (4H, m).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 155, 154.9, 129.7, 129.7, 128.5, 118.7, 118.5, 118.4, 117.3, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 48.3, 48.1, 47.9, 36, 35.7, 28.9, 25.1, 22.4.

Example 228: (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

To a stirred suspension of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (150 mg, 0.435 mmol) in dioxane (3 mL) was added 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (113 mg, 0.592 mmol) in one portion and the reaction mixture was stirred for 30 min. at room temperature. Thereupon, the obtained solution was treated with N-hydroxyacetimidamide (32.2 mg, 0.435 mmol) and the reaction mixture was stirred for 1 h at room temperature followed by stirring at 110° C. for additional 3.5 h. The solvent was then removed under vacuum and the residue was diluted with ethyl acetate (25 mL), twice with sodium bicarbonate solution (25 mL) and water (25 mL), respectively. The organic phase was dried over MgSO₄, filtered and evaporated to dryness. Purification by chromatography (reversed phase, acetonitrile-water mixture) followed by recrystallization from isopropanol afforded (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white solid. Yield: 0.058 g, 34%.

¹H NMR (DMSO_(d6)): 11.97 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=9.3, 11.7 Hz), 4.15 (2H, m), 3.75 (1H, dd, J=11.6, 7.8 Hz), 3.25 (1H, dd, J=15.9, 9.3 Hz), 2.86 (1H, dd, J=15.9, 8.0 Hz), 2.31 (3H, s).

¹³C NMR (DMSO_(d6)): 175.9, 167.1, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.1, 154.9, 154.9, 130.2, 129.7, 129.7, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 112, 48.7, 35.6, 29, 22, 11.1.

Example 229: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Step 1: ethyl (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

To a solution of (4R)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (3.22 g, 5.57 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (8.59 mL, 111 mmol) in one portion and the solution was stirred for 5 h at room temperature. Thereupon, the mixture was quenched with sodium bicarbonate solution with ice cooling. The organic phase was dried over MgSO₄, filtered and treated with methyl isothiocyanate (0.489 g, 6.69 mmol) followed by addition of triethyl amine (0.78 mL, 5.57 mmol). The solution was stirred for 64 h at room temperature, and then evaporated to dryness. The residue was dissolved in abs. ethanol (50 mL) followed by addition of cc. HCl (1.39 mL, 16.72 mmol) and the mixture was stirred under reflux for 1 h. Thereupon the solvent was removed and the residue was partitioned between dichloromethane and water. The organic phase was dried (MgSO₄), filtered and evaporated. Chromatography in a mixture of petroleumether-ethyl acetate followed by slurring in petroleum ether afforded (R)-ethyl 2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate as colorless solid. Yield: 0.25 g, 11%.

Step 2: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

To a solution of (R)-ethyl 2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate (0.25 g, 0.644 mmol) in methanol (7 mL) was added 1 N NaOH (0.97 mL, 0.966 mmol) (gentle heating and sonication to get clear solution) and the mixture was stirred for 3 h at room temperature. Methanol was then removed under vacuum, the residue was diluted with water to approx. 10 mL, acidified by addition of 6 M HCl to pH=1-2. The resulting precipitate was collected, washed with water, dried in vacuum at 50° C. to give (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid as an off-white powder. Yield: 0.21 g, 91%.

¹H NMR (DMSO_(d6)): 12.74 (1H, s br), 7.86 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.6, 9.2 Hz), 3.85 (1H, dd, J=11.7, 7.6 Hz), 3.65 (2H, s), 3.40 (3H, s), 3.35 (1H, m), 2.95 (1H, dd, J=16.0, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 156.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 128.5, 120.5, 120.4, 120.3, 115.6, 105.9, 105.7, 105.6, 49.5, 34.8, 31.4, 29.8, 29.

Example 230: (S)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from (4S)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-(5-chloro-2-fluorophenyl)pyrrolidine-1-carboxylate and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 12.70 (1H, br s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.29 (1H, dd, J=9.9, 8.9 Hz), 4.21 (2H, m), 3.81 (1H, m), 3.67 (2H, s), 3.39 (3H, m), 3.27 (1H, br dd, J=15.6, 7.5 Hz), 2.93 (1H, dd, J=15.5, 7.3 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 159.8, 158.2, 156.6, 130.2, 130.1, 128.9, 128.9, 128.7, 128.5, 128.5, 128.5, 117.6, 117.4, 115.8, 50.2, 31.4, 29.8, 29.3.

Example 231: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(3-chloro-2,6-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 12.78 (1H, br s), 7.64 (1H, m), 7.21 (1H, t, J=8.9 Hz), 4.12 (1H, d, J=12.2 Hz), 3.81 (1H, d, J=12.0 Hz), 3.74 (2H, m), 3.36 (3H, s), 2.85 (1H, dd, J=8.2, 4.4 Hz), 1.70 (1H, dd, J=8.1, 5.6 Hz), 1.27 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 170.9, 161.2, 161.2, 159.6, 159.6, 157.8, 157.8, 157, 156.2, 156.1, 117, 116.9, 116.8, 115.8, 115.7, 115.6, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 52.3, 31.4, 29.8, 25.7, 21.7, 21.1.

Example 232: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 8.38 (1H, br d, J=6.6 Hz), 7.73 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, m), 3.46 (1H, dd, J=8.9, 3.5 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.28 (1H, dd, J=15.8, 9.5 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz), 2.07 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.4, 118.8, 118.7, 118.6, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 72.4, 66.3, 49.8, 49.6, 34.8, 32, 31.5, 31.1, 29.2.

Example 233: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=9.3, 11.2 Hz), 3.79 (1H, br dd, J=11.6, 7.6 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, m), 3.27 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.3, 118.9, 118.8, 118.6, 116.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 49.5, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 234: 1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)cyclopropane-1-carboxamide

Compound was prepared analogous manner to Example 32 from (S)-(1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)cyclopropyl)(1H-imidazol-1-yl)methanone and isolated as a white powder.

¹H NMR (DMSO_(d6)): 7.74 (1H, m), 7.63 (1H, d, J=6.9 Hz), 7.18 (1H, m), 4.41 (1H, quin, J=8.9 Hz), 4.32 (1H, m), 4.21 (1H, dd, J=9.3, 11.3 Hz), 3.84-3.74 (2H, m), 3.72 (1H, dd, J=8.8, 6.7 Hz), 3.63 (1H, m), 3.46 (1H, dd, J=8.8, 4.8 Hz), 3.35 (3H, s), 3.24 (1H, dd, J=15.6, 9.0 Hz), 2.97 (1H, dd, J=15.6, 9.0 Hz), 2.04 (1H, m), 1.76 (1H, m), 1.43 (1H, m), 1.35 (1H, m), 1.02 (2H, m).

¹³C NMR (DMSO_(d6)): 170.4, 161, 160.9, 159.3, 159.3, 157.7, 157.6, 156.5, 156.1, 156, 132.6, 132.5, 130.9, 119.3, 118, 117.9, 117.7, 113.8, 113.8, 113.6, 113.6, 104.1, 103.9, 71.5, 66.6, 50.3, 49.2, 35.1, 32, 31.4, 29, 22.1, 15.5, 15.1.

Example 235: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

¹H NMR (DMSO_(d6)): 7.73 (1H, ddd, J=8.8, 8.1, 5.8 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, dd, J=11.2, 9.5 Hz), 3.90 (2H, m), 3.87 (2H, m), 3.85 (2H, s), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.36 (3H, s), 3.31 (2H, m), 3.28 (1H, dd, J=9.3, 15.8 Hz), 3.13 (2H, m), 2.86 (1H, dd, J=15.9, 8.0 Hz).

¹³C NMR (DMSO_(d6)): 167.2, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.3, 155.9, 155.9, 132.5, 132.4, 128.5, 118.8, 118.7, 118.6, 116, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.1, 51, 49.6, 43.7, 40.2, 34.8, 31.6, 29.2, 28.8.

Example 236: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.99 (1H, br d, J=7.5 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, dd, J=11.3, 9.4 Hz), 3.81 (2H, m), 3.40 (3H, s), 3.38 (2H, m), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.89 (1H, dd, J=15.8, 8.0 Hz), 1.05 (6H, d, J=6.5 Hz).

¹³C NMR (DMSO_(d6)): 166.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 156.1, 154.9, 154.9, 129.7, 129.6, 128.3, 118.8, 118.7, 118.6, 116.6, 116.1, 116, 115.9, 113.2, 113.2, 113.1, 113.1, 49.5, 40.7, 34.7, 31.4, 31.3, 29.2, 22.3, 22.3.

Example 237: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=9.4, 11.2 Hz), 3.81 (1H, dd, J=11.4, 7.9 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.56 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.28 (1H, dd, J=15.7, 9.2 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 157, 156.9, 156.3, 155.3, 155.3, 149, 149, 147.6, 147.5, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 66, 66, 49.4, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 238: (S)-1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)cyclopropane-1-carboxamide

Compound was prepared analogous manner to Example 32 from (S)-(1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)cyclopropyl)(1H-imidazol-1-yl)methanone and isolated as a light cream solid.

¹H NMR (DMSO_(d6)): 7.84 (1H, t, J=5.6 Hz), 7.74 (1H, m), 7.18 (1H, m), 4.41 (1H, quin, J=8.9 Hz), 4.21 (1H, dd, J=9.4, 10.9 Hz), 3.81 (1H, dd, J=11.2, 9.1 Hz), 3.45 (2H, q, J=6.5 Hz), 3.37 (3H, s), 3.24 (3H, m), 2.98 (3H, s), 2.98 (1H, dd, J=9.4, 15.4 Hz), 1.43 (1H, m), 1.34 (1H, m), 1.08 (1H, m), 1.04 (1H, m).

¹³C NMR (DMSO_(d6)): 170.7, 160.9, 160.9, 159.3, 159.3, 157.7, 157.6, 156.7, 156.1, 156, 132.6, 132.5, 131.2, 119.1, 117.8, 117.7, 117.6, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 52.7, 49.2, 40.6, 35.1, 33.4, 31.5, 28.9, 19.2, 15.4, 14.8.

Example 239: (R)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 8.23 (1H, d, J=7.6 Hz), 7.48 (1H, qd, J=9.4, 4.8 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.23 (1H, dd, J=9.7, 11.5 Hz), 3.95 (1H, m), 3.81 (1H, dd, J=11.4, 7.9 Hz), 3.44 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.4 Hz), 3.23 (2H, m), 3.06 (2H, m), 2.90 (1H, dd, J=8.3, 15.8 Hz), 2.05 (2H, m), 1.90 (2H, m).

¹³C NMR (DMSO_(d6)): 167.2, 157, 156.9, 156.3, 155.4, 155.3, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.8, 128.5, 118.9, 118.8, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116.3, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 49.5, 48.4, 44.1, 34.7, 31.5, 31.2, 29.2, 29.1.

Example 240: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 7.73 (1H, m), 7.51 (1H, br s), 7.17 (1H, m), 7.10 (1H, br s), 4.44 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.4 Hz), 3.80 (1H, dd, J=11.6, 7.9 Hz), 3.40 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.5, 118.7, 118.5, 118.4, 116.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.5, 34.8, 31.4, 31, 29.1.

Example 241: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, t, J=9.4 Hz), 5.04 (0.3H, t, J=5.5 Hz), 4.72 (0.7H, t, J=5.6 Hz), 4.44 (1H, m), 4.22 (1H, dd, J=9.5, 11.1 Hz), 4.02 (0.3H, q, J=6.6 Hz), 3.93 (0.7H, m), 3.79 (1.6H, m), 3.64 (1.4H, m), 3.48 (2.1H, m), 3.43-3.36 (3.9H, m), 3.27 (2H, m), 2.86 (1H, m), 1.85 (4H, m).

¹³C NMR (DMSO_(d6)): 166.8, 166.7, 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 156.1, 156, 155.9, 155.9, 132.5, 132.4, 128.3, 128.2, 118.9, 118.8, 118.8, 118.7, 116.7, 116.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 62.8, 62.8, 60.8, 58.8, 58.7, 49.6, 49.5, 46.9, 45.5, 34.8, 31.6, 31.5, 30.6, 30, 29.2, 27.8, 26.7, 23.5, 21.4.

Example 242: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.6, 9.2 Hz), 3.84 (1H, dd, J=11.6, 7.6 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.90 (1H, dd, J=15.8, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 156.3, 146.4, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 128, 120.5, 120.4, 120.3, 116.3, 105.9, 105.7, 105.6, 66, 66, 49.4, 45.6, 41.7, 34.9, 31.5, 29.1, 28.8.

Example 243: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, d, J=6.6 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.27-4.19 (2H, m), 3.84 (1H, dd, J=11.7, 7.6 Hz), 3.77 (1H, q, J=7.3 Hz), 3.72 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, br dd, J=8.9, 3.6 Hz), 3.44 (2H, s), 3.40 (3H, s), 3.31 (1H, dd, J=9.4, 16.1 Hz), 2.93 (1H, dd, J=15.8, 7.9 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 156.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.4, 105.9, 105.7, 105.6, 72.4, 66.3, 49.8, 49.4, 34.9, 32, 31.5, 31, 29.1.

Example 244: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 8.36 (1H, br d, J=6.5 Hz), 7.47 (1H, m), 7.18 (1H, t br), 4.43 (1H, quin, J=8.6 Hz), 4.29-4.16 (2H, m), 3.81 (1H, dd, J=11.6, 8.1 Hz), 3.77 (1H, m), 3.72 (1H, dd, J=9.0, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.6 Hz), 3.43 (2H, s), 3.40 (3H, s), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 157, 156.9, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149, 147.5, 147.5, 147.4, 145.9, 145.8, 145.8, 128.4, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 72.3, 66.2, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 245: (R)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.08 (1H, br d, J=7.0 Hz), 7.46 (1H, dd, J=6.5, 2.5 Hz), 7.41 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.0, 10.0 Hz), 4.20 (2H, m), 3.98 (1H, m), 3.80 (1H, m), 3.41 (2H, s), 3.39 (3H, s), 3.24 (1H, br dd, J=15.6, 7.5 Hz), 2.89 (1H, br dd, J=15.4, 7.0 Hz), 1.79 (2H, m), 1.62 (2H, m), 1.49 (2H, m), 1.36 (2H, m).

¹³C NMR (DMSO_(d6)): 167, 159.8, 158.2, 156.3, 130.3, 130.2, 128.9, 128.9, 128.5, 128.5, 128.5, 128.2, 117.6, 117.4, 116.9, 50.5, 50.1, 39.8, 32.2, 32.2, 31.4, 31.2, 29.5, 23.4.

Example 246: 2-((R)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.41 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.0, 8.9 Hz), 4.28-4.15 (3H, m), 3.78 (2H, m), 3.73 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.47 (1H, dd, J=8.9, 3.5 Hz), 3.45 (2H, s), 3.40 (3H, s), 3.24 (1H, dd, J=15.5, 7.6 Hz), 2.90 (1H, dd, J=15.4, 7.2 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 159.8, 158.2, 156.4, 130.2, 130.1, 128.9, 128.9, 128.5, 128.5, 128.4, 117.6, 117.4, 116.7, 72.4, 66.3, 50.1, 49.8, 39.8, 32, 31.5, 31, 29.4.

Example 247: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 4.43 (1H, m), 4.23 (1.35H, m), 4.04 (0.65H, m), 3.82 (1H, m), 3.79 (0.7H, m), 3.65 (1.3H, s), 3.53-3.37 (2.3H, m), 3.36, 3.35 (3H, 2 s), 3.34-3.22 (3.75H, m), 3.21 (1.95H, s), 2.92-2.84 (1H, m), 2.0-1.73 (4H, m).

¹³C NMR (DMSO_(d6)): 166.9, 166.6, 156.9, 156.9, 156.9, 156.9, 156.2, 156.1, 155.3, 155.3, 155.3, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.5, 128.2, 128.2, 118.9, 118.9, 118.8, 118.7, 116.7, 116.5, 116.4, 116.4, 116.3, 116.3, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 73.8, 71.6, 58.5, 58.3, 56.3, 56.2, 49.4, 46.8, 45.4, 34.8, 31.5, 30.6, 29.9, 29.1, 29.1, 28.2, 27.2, 23.5, 21.5.

Example 248: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 5.03 (0.3H, m), 4.76 (0.7H, quin, J=8.3 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.25 (1H, m), 3.94 (0.3H, br d, J=17.5 Hz), 3.83 (1H, dd, J=11.5, 7.8 Hz), 3.79 (1.4H, m), 3.64 (1.7H, m), 3.35 (3H, s), 3.30 (1.6H, m), 2.90 (1H, m), 2.28-1.85 (4H, m).

¹³C NMR (DMSO_(d6)): 168.6, 168.1, 156.9, 156.9, 156.4, 156.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.8, 128.6, 128.5, 127, 125.1, 123.2, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116, 115.8, 111.9, 111.8, 56.6, 56.4, 56.2, 56, 49.5, 47, 46.5, 34.8, 34.7, 31.4, 31.4, 30.4, 29.6, 29.2, 26.2, 24.8, 23.6, 21.3.

Example 249: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.62 (1H, m), 7.51 (1H, br s), 7.22 (1H, m), 7.10 (1H, br s), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, dd, J=9.3, 11.3 Hz), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.41 (2H, m), 3.40 (3H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 169.9, 160.2, 160.1, 158.5, 158.5, 156.6, 156.6, 156.2, 155, 154.9, 129.7, 129.7, 128.5, 118.7, 118.6, 118.4, 116.5, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 49.4, 34.8, 31.4, 31, 29.1.

Example 250: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=9.0, 3.4 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.29 (1H, dd, J=15.8, 9.4 Hz), 2.89 (1H, dd, J=15.8, 8.1 Hz), 2.07 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.7, 128.4, 118.8, 118.7, 118.6, 116.4, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 72.4, 66.3, 49.8, 49.5, 34.7, 32, 31.5, 31.1, 29.2.

Example 251: 2-((S)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.37 (1H, d, J=6.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.41 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=10.1, 8.8 Hz), 4.22 (3H, m), 3.79 (2H, m), 3.73 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (2H, m), 3.46 (1H, dd, J=3.6, 9.0 Hz), 3.40 (3H, s), 3.24 (1H, dd, J=15.6, 7.6 Hz), 2.90 (1H, dd, J=15.5, 7.3 Hz), 2.08 (1H, m), 1.72 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 159.8, 158.2, 156.4, 130.2, 130.1, 128.9, 128.9, 128.5, 128.5, 128.5, 128.3, 117.6, 117.4, 116.7, 72.4, 66.3, 50.1, 49.8, 39.8, 32, 31.5, 31, 29.4.

Example 252: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a yellow powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=9.7, 11.2 Hz), 3.91 (1H, m), 3.81 (1H, m), 3.80 (1H, dd, J=7.7, 11.6 Hz), 3.71 (1H, m), 3.69 (1H, m), 3.62 (1H, m), 3.56 (1H, m), 3.34 (3H, m), 3.26 (1H, m), 2.93 (1.8H, m), 2.84 (1H, m), 2.74 (1.2H, s), 2.25-2.04 (1H, m), 1.90-1.72 (1H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 156.2, 156.2, 155.9, 155.8, 132.5, 132.4, 128.3, 128.1, 118.9, 118.8, 118.6, 116.5, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 69.4, 69.3, 69.3, 69.2, 67.1, 67, 56.5, 56.5, 53, 49.5, 34.8, 31.5, 31.5, 31.2, 29.9, 29.8, 29.7, 29.7, 29.4, 29.4, 29.3, 29.2, 29.2, 27.6.

Example 253: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.78 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.7, 11.2 Hz), 4.16 (2H, d, J=5.6 Hz), 3.81 (1H, dd, J=11.4, 8.1 Hz), 3.55 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 168.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.5, 155.9, 155.9, 132.5, 132.4, 128.9, 118.6, 118.5, 118.4, 117.5, 115.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 49.5, 34.8, 31.4, 30.8, 29.1, 27.3.

Example 254: (R)-N-(1-cyanocyclopropyl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 9.03 (1H, s), 7.48 (1H, m), 7.18 (1H, br t, J=9.4 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.24 (1H, dd, J=9.5, 11.3 Hz), 3.82 (1H, dd, J=11.4, 8.1 Hz), 3.48 (2H, m), 3.37 (3H, s), 3.30 (1H, dd, J=9.2, 11.9 Hz), 2.92 (1H, dd, J=15.8, 8.3 Hz), 1.48 (2H, m), 1.14 (2H, m).

¹³C NMR (DMSO_(d6)): 169.3, 156.9, 156.5, 155.3, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 128.8, 120.6, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.5, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 34.7, 31.4, 30.8, 29.1, 19.9, 15.6, 15.6.

Example 255: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white powder.

¹H NMR (DMSO_(d6)): 8.12 (1H, br d, J=7.3 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.6, 11.3 Hz), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.72-3.59 (3H, m), 3.45 (2H, s), 3.39 (3H, s), 3.36 (1H, m), 3.29 (1H, dd, J=15.8, 9.3 Hz), 3.12 (1H, m), 2.90 (1H, dd, J=15.7, 8.2 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

¹³C NMR (DMSO_(d6)): 167.3, 157, 156.9, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 111.9, 111.8, 70.1, 67, 49.4, 45.1, 34.7, 31.5, 31.2, 29.1, 28.5, 23.8.

Example 256: (S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 234) and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 9.20 (2H, m), 7.74 (1H, m), 7.18 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.22 (1H, dd, J=9.5, 11.1 Hz), 3.91 (2H, m), 3.84 (1H, s br), 3.80 (1H, dd, J=8.1, 11.4 Hz), 3.75 (1H, dd, J=6.0, 10.2 Hz), 3.64 (1H, m), 3.47 (3H, s), 3.40 (1H, dd, J=9.6, 15.9 Hz), 3.13 (2H, br s), 3.00 (1H, dd, J=15.7, 8.4 Hz), 2.94 (2H, t, J=7.6 Hz), 2.20 (1H, m), 2.03 (1H, m).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.6, 156.6, 156, 155.9, 132.6, 132.5, 128.5, 118.5, 118.4, 118.3, 116.5, 113.8, 113.8, 113.7, 113.6, 104.1, 104.1, 104, 104, 68.9, 66.4, 57.5, 49.4, 43.5, 34.9, 31.4, 29.2, 28.9, 21.1.

Example 257: (R)-2-methyl-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 242) and isolated as a pale yellow powder.

¹H NMR (DMSO_(d6)): 11.61 (1H, br s), 7.88 (1H, m), 4.51 (1H, quin, J=8.4 Hz), 4.24 (1H, dd, J=11.3, 9.5 Hz), 3.97 (2H, br d, J=11.7 Hz), 3.85 (1H, dd, J=7.7, 11.7 Hz), 3.82 (2H, m), 3.48 (3H, s), 3.47 (2H, m), 3.43 (1H, dd, J=15.6, 8.6 Hz), 3.30 (2H, m), 3.13-2.98 (5H, m).

¹³C NMR (DMSO_(d6)): 156.7, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 127.9, 120.4, 120.3, 120.2, 116.6, 105.9, 105.8, 105.6, 63.1, 52.9, 50.8, 49.3, 34.9, 31.4, 29.2, 18.6.

Example 258: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid

To a solution of pyridin-2-amine (28.9 mg, 0.307 mmol) in N,N-dimethyl formamide (0.93 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.557 mmol). The reaction mixture was cooled in an ice bath and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (HATU) (117 mg, 0.307 mmol) and (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (100 mg, 0.279 mmol) were added in one portion. The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was then transferred to a separatory funnel, diluted with 30 mL of water and 40 mL of ethyl acetate. The aqueous layer was extracted twice with 40 mL of ethyl acetate. The organic layer was washed with brine, dried over MgSO₄, filtered and evaporated to dryness. Chromatography afforded (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide as an off-white solid. Yield: 31 mg, 25%.

¹H NMR (DMSO_(d6)): 10.76 (1H, s), 8.32 (1H, dd, J=4.8, 1.0 Hz), 8.04 (1H, br d, J=8.1 Hz), 7.78 (1H, m), 7.61 (1H, m), 7.21 (1H, m), 7.11 (1H, dd, J=7.0, 5.2 Hz), 4.46 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=9.7, 11.1 Hz), 3.81 (1H, dd, J=7.9, 11.7 Hz), 3.79 (2H, m), 3.44 (3H, m), 3.31 (1H, m), 2.92 (1H, dd, J=16.0, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.4, 154.9, 154.9, 151.7, 148, 138.2, 129.7, 129.6, 128.8, 119.6, 118.8, 118.7, 118.5, 116, 116, 116, 115.9, 115.9, 115.9, 115.8, 113.5, 113.2, 113.2, 113.1, 113, 49.5, 34.7, 31.9, 31.6, 29.2.

Example 259: (R)-2-methyl-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

Compound was prepared analogous manner to Example 229 step 1 from tert-butyl (4R)-2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 212 step 3) and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.42 (1H, d, J=1.8 Hz), 8.38 (1H, dd, J=4.7, 1.5 Hz), 7.84 (1H, m), 7.62 (1H, dt, J=7.8, 1.8 Hz), 7.28 (1H, dd, J=7.7, 4.8 Hz), 4.38 (1H, quin, J=8.4 Hz), 4.19 (1H, br dd, J=11.4, 9.2 Hz), 3.79 (1H, dd, J=11.7, 7.4 Hz), 3.45 (3H, s), 3.13 (1H, dd, J=15.7, 9.4 Hz), 2.86 (4H, m), 2.67 (1H, dd, J=15.6, 7.6 Hz).

¹³C NMR (DMSO_(d6)): 156.1, 149.7, 147.4, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 145.2, 145.2, 145.1, 145.1, 145.1, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 136, 135.9, 127.1, 123.3, 120.4, 120.3, 120.2, 120.2, 105.8, 105.7, 105.5, 49.1, 34.9, 31.2, 30.1, 29.1, 25.2.

Example 260: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid

Compound was prepared analogous manner to Example 229 step 1 from ethyl oxoacetate and (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 212 step 3) and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.33 (1H, br s), 7.86 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.81 (1H, dd, J=11.7, 7.7 Hz), 3.44 (3H, s), 3.38 (1H, dd, J=9.4, 15.2 Hz), 2.99 (1H, dd, J=15.7, 7.9 Hz), 2.73 (2H, t, J=7.3 Hz), 2.54 (2H, t, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 173.4, 156, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 126.8, 120.5, 120.4, 120.4, 120.3, 105.9, 105.7, 105.6, 49.1, 34.9, 31.4, 31.1, 29.3, 19.5.

Example 261: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.2, 9.5 Hz), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.45 (3H, s), 3.37 (3H, m), 3.25 (2H, t, J=6.9 Hz), 3.00 (1H, br dd, J=15.7, 7.9 Hz), 2.72 (2H, m), 2.53 (2H, t, J=7.7 Hz), 1.83 (2H, quin, J=6.7 Hz), 1.74 (2H, m).

¹³C NMR (DMSO_(d6)): 168.9, 155.8, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 126.7, 120.9, 120.6, 120.4, 120.3, 105.8, 105.7, 105.5, 49.1, 45.7, 45.3, 34.9, 31.5, 31.1, 29.2, 25.5, 23.9, 19.3.

Example 262: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-3-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.62 (1H, m), 7.31 (1H, br s), 7.21 (1H, m), 6.86 (1H, br s), 4.42 (1H, quin, J=8.7 Hz), 4.20 (1H, dd, J=9.3, 11.1 Hz), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.44 (3H, s), 3.32 (1H, m), 2.94 (1H, dd, J=15.7, 8.2 Hz), 2.71 (2H, t, J=7.3 Hz), 2.35 (2H, t, J=7.4 Hz).

¹³C NMR (DMSO_(d6)): 172.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.8, 155, 154.9, 129.7, 129.7, 126.8, 120.8, 118.8, 118.7, 118.6, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 49.2, 34.8, 32.5, 31.1, 29.4, 19.8.

Example 263: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.41 (1H, m), 7.31 (1H, br s), 7.14 (1H, m), 6.87 (1H, br s), 4.39 (1H, quin, J=8.8 Hz), 4.19 (1H, dd, J=10.6, 9.9 Hz), 3.75 (1H, dd, J=11.3, 8.4 Hz), 3.44 (3H, s), 3.31 (1H, br dd, J=15.5, 9.3 Hz), 2.93 (1H, dd, J=15.6, 8.7 Hz), 2.71 (2H, t, J=7.3 Hz), 2.36 (2H, t, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 172.9, 161.6, 161.6, 160, 159.9, 155.8, 129.8, 129.8, 129.7, 126.9, 120.8, 116.6, 116.5, 116.3, 112.3, 112.2, 112.1, 112.1, 49.2, 34.5, 32.5, 31.1, 29.6, 19.8.

Example 264: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.41 (1H, m), 7.14 (2H, m), 4.38 (1H, quin, J=8.8 Hz), 4.19 (1H, m), 3.75 (1H, dd, J=11.2, 8.4 Hz), 3.45 (3H, s), 3.37 (2H, m), 3.32 (1H, m), 3.25 (2H, t, J=6.8 Hz), 2.95 (1H, dd, J=15.6, 8.7 Hz), 2.72 (2H, t, J=7.7 Hz), 2.54 (2H, t, J=7.5 Hz), 1.83 (2H, m), 1.74 (2H, m).

¹³C NMR (DMSO_(d6)): 168.9, 161.6, 161.6, 160, 159.9, 155.8, 129.8, 129.7, 129.7, 127, 120.9, 116.6, 116.5, 116.3, 112.2, 112.2, 112.1, 49.2, 45.7, 45.3, 34.4, 31.5, 31.1, 29.4, 25.5, 23.9, 19.3.

Example 265: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 8.09 (1H, d, J=6.6 Hz), 7.48 (1H, m), 7.18 (1H, br t, J=9.5 Hz), 4.40 (1H, quin, J=8.6 Hz), 4.20 (1H, dd, J=9.4, 11.5 Hz), 4.19 (1H, m), 3.78 (1H, dd, J=11.4, 7.9 Hz), 3.74-3.66 (2H, m), 3.63 (1H, m), 3.44 (3H, s), 3.38 (1H, dd, J=8.9, 3.6 Hz), 3.33 (1H, m), 2.92 (1H, dd, J=15.6, 8.1 Hz), 2.72 (2H, t, J=7.3 Hz), 2.37 (2H, t, J=7.3 Hz), 2.03 (1H, m), 1.62 (1H, m).

¹³C NMR (DMSO_(d6)): 170.5, 156.9, 156.9, 155.9, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 145.8, 126.8, 120.6, 119, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.2, 49.5, 49.1, 34.7, 32.6, 32.1, 31.1, 29.5, 19.9.

Example 266: (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.48 (1H, m), 7.18 (1H, t, J=9.4 Hz), 4.40 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.3 Hz), 3.78 (1H, dd, J=11.5, 8.1 Hz), 3.51 (4H, m), 3.45 (3H, s), 3.41 (4H, m), 3.38 (1H, m), 2.98 (1H, dd, J=15.6, 8.4 Hz), 2.72 (2H, m), 2.63 (2H, m).

¹³C NMR (DMSO_(d6)): 169.6, 157, 156.9, 155.8, 155.3, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.8, 126.8, 120.8, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 111.8, 66.1, 66, 49.1, 45.1, 41.5, 34.8, 31.1, 29.7, 29.3, 19.6.

Example 267: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a white powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, br t, J=9.5 Hz), 4.92 (0.35H, t, J=5.7 Hz), 4.72 (0.65H, t, J=5.7 Hz), 4.40 (1H, m), 4.20 (1H, br t, J=10.3 Hz), 3.90 (1H, m), 3.77 (1H, m), 3.46 (0.65H, m), 3.45 (3H, s), 3.42-3.27 (3H, m), 3.26-3.15 (1.35H, m), 2.97 (1H, m), 2.71 (2H, m), 2.68-2.51 (2H, m), 1.94-1.68 (4H, m).

¹³C NMR (DMSO_(d6)): 169.6, 169.6, 156.9, 156.9, 155.8, 155.8, 155.3, 155.3, 149.1, 149, 147.5, 147.5, 145.9, 145.9, 145.8, 145.8, 126.8, 126.8, 120.9, 120.9, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 62.6, 61, 58.6, 58.5, 49.1, 46.5, 45.3, 34.8, 31.6, 31.3, 31.1, 29.3, 26.6, 23.3, 21.3, 19.2.

Example 268: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide

Compound was prepared analogous manner to Example 168 from (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 10.54 (1H, s), 8.27 (1H, ddd, J=0.7, 1.8, 4.8 Hz), 8.01 (1H, br d, J=8.4 Hz), 7.75 (1H, m), 7.57 (1H, m), 7.12 (1H, m), 7.08 (1H, ddd, J=7.3, 4.9, 1.0 Hz), 4.38 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.4 Hz), 3.74 (1H, dd, J=11.7, 7.6 Hz), 3.47 (3H, s), 3.33 (1H, dd, J=15.8, 9.5 Hz), 2.90 (1H, dd, J=15.6, 7.7 Hz), 2.82 (2H, m), 2.69 (2H, m).

¹³C NMR (DMSO_(d6)): 170.8, 160, 160, 158.4, 158.3, 156.5, 156.4, 155.9, 154.8, 154.8, 151.8, 147.6, 138.4, 129.6, 129.6, 127.1, 120.3, 119.3, 118.9, 118.8, 118.7, 116, 116, 115.9, 115.9, 113.4, 113.1, 113.1, 113, 113, 49.3, 34.7, 33.8, 31.1, 29.4, 21.6, 19.7.

Example 269: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide

Compound was prepared analogous manner to Example 168 from (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 10.52 (1H, s), 8.28 (1H, ddd, J=0.9, 1.9, 4.9 Hz), 8.03 (1H, br d, J=8.2 Hz), 7.75 (1H, m), 7.38 (1H, m), 7.09 (1H, ddd, J=1.0, 4.9, 7.4 Hz), 7.06 (2H, m), 4.36 (1H, quin, J=8.7 Hz), 4.17 (1H, dd, J=9.7, 11.3 Hz), 3.73 (1H, dd, J=11.4, 8.0 Hz), 3.48 (3H, s), 3.31 (1H, dd, J=15.6, 9.4 Hz), 2.90 (1H, dd, J=15.7, 8.4 Hz), 2.82 (2H, m), 2.70 (2H, m).

¹³C NMR (DMSO_(d6)): 170.8, 161.5, 161.4, 159.9, 159.8, 155.9, 151.9, 147.8, 138.2, 129.7, 129.7, 129.6, 127.2, 120.3, 119.3, 116.6, 113.3, 112.1, 112.1, 112, 112, 49.4, 34.3, 33.8, 31.1, 29.6, 19.7.

Example 270: (R)-N-(cyanomethyl)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 34 from (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.60 (1H, t, J=5.6 Hz), 7.47 (1H, m), 7.17 (1H, t, J=9.6 Hz), 4.41 (1H, quin, J=8.6 Hz), 4.19 (1H, dd, J=9.7, 11.3 Hz), 4.11 (2H, m), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.44 (3H, s), 3.31 (1H, dd, J=9.2, 15.5 Hz), 2.93 (1H, dd, J=15.6, 8.1 Hz), 2.76 (2H, t, J=7.3 Hz), 2.45 (2H, t, J=7.3 Hz).

¹³C NMR (DMSO_(d6)): 171.5, 156.9, 156.9, 156, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 127, 120.2, 118.9, 118.8, 118.8, 118.7, 117.6, 116.5, 116.4, 116.4, 116.3, 112, 111.9, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 49.2, 34.7, 32.4, 31.1, 29.3, 27, 19.6.

Example 271: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.12 (1H, br d, J=7.0 Hz), 7.64 (1H, td, J=8.6, 5.6 Hz), 7.21 (1H, td, J=1.0, 9.0 Hz), 4.10 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.79 (1H, d, J=12.2 Hz), 3.47 (2H, m), 3.35 (3H, s), 2.78 (1H, dd, J=8.4, 4.4 Hz), 1.80 (2H, m), 1.69 (1H, dd, J=8.2, 5.6 Hz), 1.63 (2H, m), 1.50 (2H, m), 1.39 (2H, m), 1.25 (1H, t, J=4.9 Hz).

¹³C NMR (DMSO_(d6)): 167.1, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.7, 156.2, 156.1, 130.5, 130.3, 130.2, 117.1, 116.9, 116.8, 116.7, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 52.2, 50.5, 32.2, 32.2, 31.4, 31.2, 25.6, 23.4, 21.7, 21.3.

Example 272: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.10 (1H, d, J=7.2 Hz), 7.58 (1H, dd, J=2.5, 6.7 Hz), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.85 (1H, d, J=12.0 Hz), 3.47 (2H, m), 3.34 (3H, s), 2.87 (1H, dd, J=8.4, 4.1 Hz), 1.81 (2H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.63 (2H, m), 1.51 (2H, m), 1.39 (2H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.1, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 50.5, 32.2, 32.2, 31.5, 31.4, 31.2, 23.4, 22.1, 20.7.

Example 273: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.11 (1H, d, J=7.2 Hz), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.85 (1H, d, J=12.0 Hz), 3.47 (2H, d, J=5.6 Hz), 3.35 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.81 (2H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.63 (2H, m), 1.51 (2H, m), 1.39 (2H, dq, J=12.9, 6.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.1, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 117.6, 117.4, 116.3, 52.4, 50.6, 32.2, 32.2, 31.5, 31.4, 31.2, 23.4, 22.1, 20.8.

Example 274: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.42 (1H, d, J=6.6 Hz), 7.64 (1H, td, J=8.6, 5.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.25 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.68 (1H, td, J=8.2, 5.6 Hz), 3.50 (2H, m), 3.48 (1H, dd, J=3.6, 8.9 Hz), 3.35 (3 H, s), 2.78 (1H, dd, J=8.4, 4.4 Hz), 2.09 (1H, dq, J=12.7, 7.6 Hz), 1.73 (1H, m), 1.69 (1H, dd, J=8.4, 5.6 Hz), 1.26 (1H, t, J=4.9 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.2, 156.1, 130.6, 130.3, 130.2, 117.1, 116.9, 116.8, 116.5, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 72.3, 66.3, 52.2, 49.8, 32.1, 31.5, 31, 25.6, 21.7, 21.2.

Example 275: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 12.79 (1H, br s), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.16 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.73 (2H, m), 3.35 (3H, s), 2.97 (1H, dd, J=8.4, 4.3 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.9, 161.8, 160.2, 157.1, 133, 133, 132.4, 132.3, 131.2, 129.1, 129, 118, 117.8, 116.2, 116.2, 115.2, 52.5, 52.5, 31.5, 31.4, 29.7, 22.1, 20.5.

Example 276: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 12.77 (1H, m), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.16 (1H, d, J=12.0 Hz), 3.87 (1H, d, J=12.0 Hz), 3.73 (2H, m), 3.36 (3H, s), 2.97 (1H, dd, J=8.4, 4.2 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170.9, 161.3, 159.6, 157.1, 131.2, 130.2, 130.1, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 115.2, 52.4, 52.4, 31.6, 31.4, 29.7, 22.1, 20.6.

Example 277: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.15 (1H, br d, J=7.3 Hz), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=2.5, 4.5, 8.5 Hz), 7.24 (1H, dd, J=8.8, 10.1 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.73-3.67 (2H, m), 3.65 (1H, m), 3.52 (2H, m), 3.37 (1H, m), 3.14 (1H, m), 3.34 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.83 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.69 (1H, m), 1.49 (2H, m), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 70.1, 67, 52.4, 45.2, 31.5, 31.4, 31.1, 28.6, 23.9, 22.1, 20.7.

Example 278: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.13 (1H, br d, J=7.3 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.4, 9.2 Hz), 3.84 (1H, dd, J=11.7, 7.7 Hz), 3.72-3.59 (3H, m), 3.45 (2H, s), 3.40 (3H, s), 3.36 (1H, m), 3.30 (1H, dd, J=9.4, 16.0 Hz), 3.12 (1H, m), 2.92 (1H, dd, J=15.9, 7.8 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

¹³C NMR (DMSO_(d6)): 167.3, 156.2, 146.4, 146.3, 146.3, 145.4, 145.3, 145.3, 145.3, 145.2, 144.9, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 144.6, 144.6, 143.8, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.5, 105.9, 105.7, 105.6, 70.1, 67, 49.4, 45.1, 34.9, 31.5, 31.2, 29.1, 28.5, 23.8.

Example 279: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.40 (1H, d, J=6.6 Hz), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.68 (1H, td, J=8.2, 5.6 Hz), 3.56-3.45 (3H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 2.10 (1H, m), 1.74 (1H, m), 1.70 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 116.1, 72.3, 66.3, 52.4, 49.8, 32.1, 31.5, 31.4, 31, 22.1, 20.7.

Example 280: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.53 (1H, br s), 7.24 (1H, dd, J=10.0, 8.8 Hz), 7.14 (1H, br s), 4.14 (1H, d, J=11.9 Hz), 3.85 (1H, d, J=12.0 Hz), 3.49 (2H, m), 3.35 (3H, s), 2.93 (1H, dd, J=8.4, 4.1 Hz), 1.67 (1H, dd, J=8.3, 5.4 Hz), 1.17 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 170, 161.8, 160.1, 156.8, 133, 133, 132.3, 132.3, 131.1, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 52.5, 52.4, 31.5, 31.4, 30.9, 22.1, 20.6.

Example 281: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.41 (1H, br d, J=6.6 Hz), 7.47 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=8.9, 9.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (1H, q, J=7.5 Hz), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.68 (1H, m), 3.56-3.46 (3H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 2.10 (1H, dq, J=12.7, 7.6 Hz), 1.74 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.3, 159.6, 156.8, 131, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.1, 72.3, 66.3, 52.4, 49.8, 32.1, 31.6, 31.5, 31, 22.1, 20.7.

Example 282: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.53 (1H, br s), 7.48 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.30 (1H, dd, J=9.8, 9.0 Hz), 7.14 (1H, br s), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.49 (2H, m), 3.35 (3H, s), 2.93 (1H, dd, J=8.4, 4.1 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, m).

¹³C NMR (DMSO_(d6)): 170, 161.3, 159.6, 156.8, 131.1, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 116.2, 52.4, 31.5, 31.4, 30.9, 22.1, 20.6.

Example 283: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.48 (1H, quin, J=8.4 Hz), 4.29-4.18 (1.35H, m), 4.04 (0.65H, m), 3.88-3.82 (1H, m), 3.79 (0.65H, m), 3.66 (1.35H, s), 3.54-3.41 (1.65H, m), 3.40 (1H, m), 3.37, 3.36 (3H, 2 s), 3.32-3.23 (3.4H, m), 3.22 (1.95H, s), 2.91 (1H, m), 2.0-1.73 (4H, m).

¹³C NMR (DMSO_(d6)): 166.9, 166.6, 156.3, 156.1, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 128.1, 128, 120.5, 120.4, 120.3, 116.8, 116.3, 105.9, 105.7, 105.6, 73.8, 71.6, 58.5, 58.3, 56.3, 56.2, 49.4, 46.8, 45.4, 34.9, 31.5, 30.6, 29.8, 29, 29, 28.2, 27.1, 23.5, 21.5.

Example 284: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.01 (1H, br d, J=7.6 Hz), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=2.6, 4.5, 8.5 Hz), 7.24 (1H, dd, J=10.1, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 3.90-3.80 (2H, m), 3.46 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz), 1.07 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.7, 161.8, 160.1, 156.8, 133.1, 133, 132.3, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 40.7, 31.5, 31.4, 31.2, 22.3, 22.3, 22, 20.7.

Example 285: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide

Compound was prepared analogous manner to Example 258 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 9.17 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.4, 9.5 Hz), 3.90 (2H, m), 3.82 (1H, dd, J=11.6, 7.8 Hz), 3.42 (3H, s), 3.31 (1H, m), 2.92 (1H, dd, J=16.0, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 160.2, 160.1, 158.7, 158.5, 158.5, 156.6, 156.5, 154.9, 154.9, 148.9, 129.7, 129.7, 129.3, 118.8, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 49.6, 34.7, 31.6, 30.9, 29.1.

Example 286: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 11.45 (1H, br s), 7.87 (1H, s), 7.47 (1H, m), 7.18 (1H, m), 7.10 (1H, s), 4.44 (1H, quin, J=8.6 Hz), 4.25 (1H, dd, J=9.6, 11.2 Hz), 3.83 (1H, dd, J=11.5, 8.0 Hz), 3.79 (2H, br s), 3.41 (3H, s), 3.33 (1H, m), 2.94 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 166.7, 157, 156.9, 156.5, 155.3, 155.3, 155.3, 153, 149.1, 149, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 136.2, 129.1, 126.7, 118.8, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.1, 112, 112, 112, 111.8, 111.8, 111.8, 49.5, 34.7, 31.6, 31.4, 29.1.

Example 287: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-4-yl)acetamide hydrochloride

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 12.16 (1H, s), 8.71 (2H, d, J=7.2 Hz), 8.13 (2H, d, J=7.2 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=9.6, 11.3 Hz), 3.97 (2H, m), 3.83 (1H, dd, J=11.6, 7.8 Hz), 3.45 (3H, s), 3.37 (1H, dd, J=9.3, 16.0 Hz), 2.95 (1H, dd, J=16.0, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 169.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.6, 156.5, 154.9, 154.9, 152.6, 142.6, 129.7, 129.7, 129.4, 118.8, 118.7, 118.5, 116.1, 116, 115.9, 115.9, 114.7, 114.4, 113.3, 113.2, 113.1, 113.1, 49.6, 34.7, 32.5, 31.7, 29.3.

Example 288: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)propanamide

Compound was prepared analogous manner to Example 34 from (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.82 (1H, d, J=7.5 Hz), 7.48 (1H, m), 7.18 (1H, br t, J=9.4 Hz), 4.40 (1H, quin, J=8.6 Hz), 4.20 (1H, dd, J=11.2, 9.3 Hz), 3.78 (1H, dd, J=11.6, 7.9 Hz), 3.66-3.58 (3H, m), 3.44 (3H, m), 3.34 (1H, m), 3.32 (1H, m), 3.04 (1H, m), 2.92 (1H, dd, J=15.7, 8.2 Hz), 2.72 (2H, t, J=7.3 Hz), 2.38 (2H, m), 1.74 (1H, m), 1.61 (1H, m), 1.40 (2H, m).

¹³C NMR (DMSO_(d6)): 170.3, 156.9, 156.9, 156.9, 155.9, 155.5, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 126.8, 120.6, 118.9, 118.9, 118.8, 118.7, 116.5, 116.5, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 70.2, 67, 49.1, 44.8, 34.8, 32.6, 31.1, 29.5, 28.6, 23.8, 19.9.

Example 289: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, d, J=6.6 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.23 (2H, m), 3.81 (1H, dd, J=10.9, 7.4 Hz), 3.77 (1H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.7 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.29 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, dd, J=15.8, 8.3 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 157, 156.9, 156.9, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.7, 118.6, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 290: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.67 (1H, br t, J=5.9 Hz), 8.50 (1H, d, J=1.8 Hz), 8.44 (1H, dd, J=4.7, 1.3 Hz), 7.70 (1H, m), 7.62 (1H, m), 7.37 (1H, dd, J=7.8, 4.8 Hz), 7.22 (1H, m), 4.41 (1H, quin, J=8.6 Hz), 4.31 (2H, m), 4.22 (1H, dd, J=9.5, 11.0 Hz), 3.80 (1H, dd, J=11.5, 8.0 Hz), 3.52 (2H, m), 3.38 (3H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 168, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 148.4, 147.7, 135.7, 135, 129.7, 129.7, 128.5, 123.6, 118.6, 118.5, 118.4, 116.1, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 49.4, 39.8, 34.7, 31.4, 31.2, 29.1.

Example 291: (S)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.52 (1H, t, J=5.9 Hz), 7.62 (1H, m), 7.22 (1H, m), 6.81 (2H, m), 6.72 (1H, m), 5.95 (2H, m), 4.41 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.4 Hz), 4.17 (2H, m), 3.79 (1H, dd, J=11.6, 8.1 Hz), 3.49 (2H, m), 3.39 (3H, s), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.83 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 147.2, 146.1, 133, 129.7, 129.7, 128.4, 120.6, 118.6, 118.5, 118.4, 116.3, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 108.1, 108, 100.8, 49.4, 42.2, 34.7, 31.4, 31.3, 29.1.

Example 292: 1-((R)-3-fluoropyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white solid.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 5.36 (1H, m t, J=52 Hz), 4.44 (1H, m), 4.24 (1H, m), 3.87-3.52 (6H, m), 3.51-3.40 (0.5H, m), 3.37 (3H, s), 3.31-3.24 (1.5H, m), 2.88 (1H, m), 2.29-1.92 (2H, m).

¹³C NMR (DMSO_(d6)): 166.6, 166.5, 156.9, 156.9, 156.3, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.1, 116, 112, 111.8, 94.2, 93, 92.6, 91.4, 62.8, 54.9, 52.8, 52.6, 52.4, 52.3, 49.4, 43.8, 43.5, 34.7, 32.1, 32, 31.5, 30.5, 30.4, 30.2, 29.1, 29.1.

Example 293: (R)-N-(2-hydroxyethyl)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, br t, J=9.7 Hz), 4.93 (0.6H, t, J=5.3 Hz), 4.67 (0.4H, t, J=5.4 Hz), 4.43 (1H, m), 4.24 (1H, br t, J=10.3 Hz), 3.81 (1H, dd, J=11.6, 8.1 Hz), 3.79 (1.2H, s), 3.71 (0.8H, s), 3.56 (1.2H, q, J=5.3 Hz), 3.47 (0.8H, q, J=5.8 Hz), 3.42 (1.2H, m), 3.35 (0.8H, m), 3.35 (3H, s), 3.32-3.21 (1H, m), 3.06 (1.2H, s), 2.88 (1H, m), 2.84 (1.8H, s).

¹³C NMR (DMSO_(d6)): 168.3, 167.9, 157, 156.9, 156.2, 156.1, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.2, 128.1, 118.9, 118.9, 118.8, 118.8, 118.8, 118.7, 118.7, 118.6, 116.9, 116.6, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 58.5, 58.3, 51.4, 50, 49.4, 36.3, 34.7, 33.2, 31.5, 29.4, 29.1, 29, 29.

Example 294: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.01 (1H, d, J=7.8 Hz), 7.58 (1H, dd, J=2.5, 8.9 Hz), 7.55 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.55 (1H, m), 3.47 (2H, m), 3.34 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.75 (2H, m), 1.70 (1H, dd, J=5.5, 8.4 Hz), 1.67 (2H, m), 1.55 (1H, m), 1.25 (2H, m), 1.21-1.08 (4H, m).

¹³C NMR (DMSO_(d6)): 166.6, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 47.8, 32.4, 32.3, 31.5, 31.4, 31.2, 25.2, 24.5, 22, 20.7.

Example 295: 2-((R)-2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.23 (2H, m), 3.84 (1H, dd, J=11.6, 7.6 Hz), 3.78 (1H, q, J=7.3 Hz), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=9.0, 3.6 Hz), 3.43 (2H, m), 3.40 (3H, m), 3.31 (1H, dd, J=9.2, 15.8 Hz), 2.93 (1H, dd, J=16.0, 7.9 Hz), 2.08 (1H, m), 1.71 (1.5H, m).

¹³C NMR (DMSO_(d6)): 167.6, 156.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.4, 116.4, 105.9, 105.7, 105.6, 72.4, 66.3, 49.8, 49.4, 34.9, 32, 31.5, 31.1, 29.1. Example 296: 1-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white solid.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.53-4.30 (3.25H, m), 4.24 (1H, m), 4.13 (0.75H, m), 3.82 (1.25H, m), 3.70 (1.5H, s), 3.70 (0.25H, m), 3.56-3.42 (1.75H, m), 3.37, 3.36 (3H, 2 s), 3.32-3.24 (1.25H, m), 2.89 (1H, m), 2.05-1.77 (4H, m).

¹³C NMR (DMSO_(d6)): 167.1, 167, 156.9, 156.9, 156.3, 156.2, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.5, 116.4, 116.4, 116.3, 116.1, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 84.6, 83.5, 83.1, 82, 56.4, 56.3, 56.2, 56.1, 49.5, 46.9, 45.7, 34.8, 34.7, 31.5, 30.5, 29.7, 29.7, 29.1, 27.3, 27.3, 26.5, 26.5, 23.8, 21.5.

Example 297: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.12 (1H, d, J=7.6 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.6, 9.2 Hz), 3.84 (1H, dd, J=7.6, 11.7 Hz), 3.81 (2H, m), 3.75 (1H, m), 3.42 (2H, s), 3.40 (3H, s), 3.36-3.28 (3H, m), 2.93 (1H, dd, J=15.8, 7.9 Hz), 1.69 (2H, m), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 156.2, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.5, 105.9, 105.7, 105.6, 65.8, 49.4, 45.2, 34.9, 32.4, 32.4, 31.5, 31.3, 29.1.

Example 298: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.80 (1H, t, J=6.3 Hz), 7.58 (1H, dd, J=2.5, 6.7 Hz), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.0, 8.8 Hz), 4.15 (1H, d, J=12.0 Hz), 3.95 (2H, m), 3.86 (1H, d, J=12.0 Hz), 3.64 (2H, m), 3.34 (3H, s), 2.91 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.15 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.9, 161.8, 160.1, 157.1, 133, 133, 132.4, 132.3, 131.4, 129.1, 129, 127.5, 125.6, 123.8, 121.9, 118, 117.8, 116.2, 116.2, 115.3, 52.5, 52.4, 31.5, 31.3, 30.8, 22.8, 22, 20.6.

Example 299: (R)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

¹H NMR (DMSO_(d6)): 8.12 (1H, d, J=7.6 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.7, 11.3 Hz), 3.79 (3H, m), 3.75 (1H, m), 3.42 (2H, m), 3.40 (3H, s), 3.33 (2H, m), 3.29 (1H, dd, J=9.3, 15.7 Hz), 2.90 (1H, dd, J=15.7, 8.2 Hz), 1.69 (2H, m d), 1.38 (2H, m q).

¹³C NMR (DMSO_(d6)): 166.8, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 145.8, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 65.8, 49.4, 45.2, 34.7, 32.4, 31.5, 31.3, 29.2.

Example 300: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.80 (1H, t, J=6.3 Hz), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.95 (2H, m), 3.86 (1H, d, J=12.0 Hz), 3.64 (2H, m), 3.34 (3H, s), 2.91 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.4, 5.3 Hz), 1.16 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.9, 161.3, 159.6, 157.1, 131.4, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 127.5, 125.6, 123.8, 121.9, 117.6, 117.4, 115.3, 52.4, 52.4, 39.9, 31.5, 31.3, 30.8, 22, 20.6.

Example 301: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.15 (1H, d, J=7.3 Hz), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.0, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.70 (2H, m), 3.65 (1H, m), 3.52 (2H, m), 3.38 (1H, m), 3.34 (3H, s), 3.14 (1H, m), 2.88 (1H, dd, J=8.4, 4.1 Hz), 1.83 (1H, m), 1.70 (1H, dd, J=5.5, 8.4 Hz), 1.68 (1H, m), 1.49 (2H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 70.1, 67, 52.4, 52.4, 45.2, 31.5, 31.4, 31.1, 28.6, 23.9, 22.1, 20.7.

Example 302: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.01 (1H, d, J=7.8 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.55 (1H, m), 3.48 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.75 (2H, br d, J=11.2 Hz), 1.70 (1H, dd, J=5.4, 8.3 Hz), 1.69 (2H, m), 1.55 (1H, m), 1.25 (2H, m), 1.15 (4H, m). 166.6, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 47.8, 32.4, 32.3, 31.5, 31.4, 31.2, 25.2, 24.5, 22, 20.8.

Example 303: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a grey solid.

¹H NMR (DMSO_(d6)): 8.02 (1H, d, J=7.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.4, 2.7 Hz), 7.30 (1H, dd, J=10.0, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (2H, m), 3.46 (2H, d, J=7.3 Hz), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.2 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.14 (1H, t, J=4.8 Hz), 1.07 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 166.7, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 40.7, 31.5, 31.4, 31.2, 22.3, 22.3, 22.1, 20.7.

Example 304: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.77 (1H, t, J=5.6 Hz), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.8, 8.9 Hz), 4.18 (2H, d, J=5.6 Hz), 4.16 (1H, d, J=12.0 Hz), 3.87 (1H, d, J=12.0 Hz), 3.63 (2H, m), 3.34 (3H, s), 2.92 (1H, dd, J=8.4, 4.3 Hz), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.18 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.7, 161.2, 159.6, 157.1, 131.4, 130.2, 130.1, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.5, 117.4, 115.1, 52.4, 31.6, 31.3, 30.7, 27.3, 22.1, 20.6.

Example 305: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

¹H NMR (DMSO_(d6)): 8.77 (1H, t, J=5.6 Hz), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.24 (1H, dd, J=8.7, 10.2 Hz), 4.18 (2H, d, J=5.6 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.63 (2H, m), 3.34 (3H, s), 2.92 (1H, dd, J=8.4, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.4 Hz), 1.18 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 168.7, 161.8, 160.1, 157.1, 133, 133, 132.4, 132.3, 131.4, 129.1, 129, 118, 117.8, 117.5, 116.2, 116.2, 115.1, 52.5, 31.5, 31.3, 30.7, 27.3, 22.1, 20.6.

Example 306: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 8.39 (1H, br d, J=6.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.1, 9.9 Hz), 4.26 (1H, m), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=9.0, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.6, 9.0 Hz), 3.34 (3H, s), 2.89 (1H, dd, J=8.3, 4.2 Hz), 2.10 (1H, dq, J=12.7, 7.6 Hz), 1.75 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.3, 159.6, 156.8, 131, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.1, 72.4, 66.3, 52.4, 52.4, 49.8, 32, 31.5, 31.4, 31, 22.1, 20.7.

Example 307: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

¹H NMR (DMSO_(d6)): 11.66 (1H, s), 8.23 (1H, br d, J=6.6 Hz), 7.56 (3H, m), 7.24 (2H, dd, J=10.1, 8.5 Hz), 4.24 (1H, m), 4.07 (1H, d, J=12.0 Hz), 3.78 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.49 (1H, dd, J=8.9, 3.7 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.4, 4.1 Hz), 2.08 (1H, m), 1.75 (1H, m), 1.66 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.8, 160.1, 155.9, 133, 132.3, 132.3, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 113.9, 72.4, 66.3, 51.5, 49.8, 32.2, 32, 31.2, 22.1, 20.7.

Example 308: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.39 (1H, d, J=6.6 Hz), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.80 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.7, 9.0 Hz), 3.35 (3H, s), 2.89 (1H, dd, J=8.3, 4.2 Hz), 2.09 (1H, m), 1.75 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.7, 161.8, 160.1, 156.8, 133, 133, 132.3, 132.3, 131, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 116.1, 72.4, 66.3, 52.4, 49.8, 32, 31.5, 31.4, 31, 22.1, 20.7.

Example 309: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=8.9, 9.8 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.72 (2H, m), 3.52 (2H, t, J=6.8 Hz), 3.34 (3H, s), 3.32 (2H, t, J=7.1 Hz), 2.87 (1H, dd, J=8.2, 4.3 Hz), 1.91 (2H, quin, J=6.7 Hz), 1.79 (2H, quin, J=6.8 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 161.3, 159.6, 156.8, 130.7, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116, 52.4, 52.4, 46.1, 45.6, 31.6, 31.5, 30.4, 25.6, 24, 22.1, 20.7.

Example 310: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.43 (2H, m), 7.00 (1H, dd, J=9.8, 8.6 Hz), 4.23 (1H, d, J=12.2 Hz), 3.99 (1H, d, J=12.0 Hz), 3.53 (2H, s), 3.46 (3H, s), 3.43 (4H, m), 2.59 (1H, dd, J=8.3, 4.2 Hz), 1.98 (2H, m), 1.87 (2H, m), 1.61 (1H, dd, J=8.2, 5.6 Hz), 1.15 (1H, m).

¹³C NMR (DMSO_(d6)): 166.4, 162.7, 161.1, 158.7, 133.8, 133.8, 133, 132.9, 131.4, 129.4, 129.3, 118.2, 118.1, 117.1, 117.1, 116, 53.4, 53.4, 47.4, 46.7, 32.4, 32.3, 32.1, 26.8, 24.9, 22.6, 21.7.

Example 311: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.1, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.51-3.40 (4H, m), 3.32 (3H, s), 2.87 (1H, dd, J=8.4, 4.1 Hz), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.59 (2H, m), 1.53 (2H, m), 1.45 (2H, m), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 161.3, 159.6, 156.9, 130.6, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 46.2, 42.3, 31.6, 31.5, 29.1, 26, 25.2, 23.9, 22.1, 20.7.

Example 312: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.56 (2H, m), 7.24 (1H, dd, J=10.0, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.46 (4H, m), 3.32 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.71 (1H, dd, J=8.2, 5.4 Hz), 1.59 (2H, m), 1.53 (2H, m), 1.45 (2H, m), 1.11 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 161.8, 160.1, 156.9, 133, 133, 132.3, 132.3, 130.6, 129.1, 129, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 46.2, 42.3, 31.5, 31.4, 29.1, 26, 25.2, 23.9, 22.1, 20.7.

Example 313: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 8.14 (1H, d, J=7.6 Hz), 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.4, 2.8 Hz), 7.30 (1H, t, J=9.3 Hz), 4.14 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.82 (2H, dt, J=11.2, 3.1 Hz), 3.78 (1H, m), 3.50 (2H, m), 3.35 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.71 (3H, m), 1.41 (2H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 65.8, 52.4, 52.4, 45.2, 32.4, 32.4, 31.5, 31.4, 31.2, 22, 21.6, 20.8.

Example 314: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.14 (1H, d, J=7.6 Hz), 7.58 (1H, m), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.82 (2H, m), 3.77 (1H, m), 3.50 (2H, m), 3.35 (3H, s), 3.34 (2H, m), 2.88 (1H, dd, J=8.4, 4.1 Hz), 1.72 (2H, m), 1.71 (1H, dd, J=5.4, 8.5 Hz), 1.41 (2H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.8, 160.1, 156.8, 133.1, 133, 132.3, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 65.8, 52.4, 52.4, 45.2, 32.4, 32.3, 31.5, 31.4, 31.2, 22, 20.7.

Example 315: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 8.77 (1H, br t, J=6.2 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.4, 9.3 Hz), 3.93 (2H, m), 3.85 (1H, dd, J=11.6, 7.6 Hz), 3.57 (2H, m), 3.39 (3H, s), 3.32 (1H, dd, J=9.2, 16.0 Hz), 2.93 (1H, dd, J=15.9, 8.0 Hz).

¹³C NMR (DMSO_(d6)): 168.7, 156.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.6, 127.5, 125.6, 123.8, 121.9, 120.4, 120.3, 120.2, 115.7, 105.9, 105.7, 105.6, 49.4, 39.5, 34.9, 31.4, 30.9, 29.

Example 316: (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.45 (1H, br s), 7.87 (1H, d, J=0.9 Hz), 7.85 (1H, m), 7.10 (1H, d, J=0.9 Hz), 4.49 (1H, quin, J=8.5 Hz), 4.26 (1H, dd, J=11.4, 9.3 Hz), 3.86 (1H, dd, J=11.7, 7.7 Hz), 3.74 (2H, m), 3.41 (3H, m), 3.37 (1H, dd, J=16.0, 8.4 Hz), 2.96 (1H, dd, J=16.0, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 156.5, 152.9, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 136.2, 128.9, 126.6, 120.4, 120.3, 120.2, 115.2, 105.9, 105.7, 105.6, 49.5, 34.8, 31.6, 31.4, 29.1, 29.

Example 317: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.44 (1H, br s), 7.87 (1H, s), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, t, J=9.3 Hz), 7.10 (1H, s), 4.45 (1H, quin, J=8.6 Hz), 4.24 (1H, m), 3.82 (1H, dd, J=11.6, 7.8 Hz), 3.78 (2H, br), 3.41 (3H, s), 3.31 (1H, m), 2.92 (1H, dd, J=16.0, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 166.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.5, 154.9, 154.9, 152.9, 152.9, 136.2, 129.7, 129.7, 129.1, 126.6, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 115.1, 113.2, 113.2, 113.1, 113.1, 49.6, 34.7, 31.6, 31.4, 29.1.

Example 318: (R)-3-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a yellowish powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.22 (1H, br dd, J=11.4, 9.2 Hz), 3.81 (1H, dd, J=11.7, 7.8 Hz), 3.52 (4H, m), 3.45 (3H, s), 3.41 (4H, m), 3.38 (1H, m), 3.01 (1H, br dd, J=15.6, 8.0 Hz), 2.72 (2H, br t, J=7.3 Hz), 2.62 (2H, t, J=7.6 Hz).

¹³C NMR (DMSO_(d6)): 169.5, 155.8, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 126.7, 120.8, 120.5, 120.4, 120.3, 105.9, 105.7, 105.5, 66, 66, 49.1, 45.1, 41.5, 34.9, 31.1, 29.7, 29.2, 19.6.

Example 319: 1-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.43 (1H, m), 4.20 (1H, m), 3.79 (1H, m), 3.60 (1H, m), 3.44 (3H, s), 3.40-3.29 (3H, m), 3.26 (1H, dd, J=12.4, 7.8 Hz), 2.97 (1H, m), 2.69 (2H, m), 2.49 (2H, m), 1.42 (1H, m), 1.36 (1H, m), 0.98 (3H, 2 s), 0.77 (3H, 2 s).

¹³C NMR (DMSO_(d6)): 168.7, 155.9, 155.8, 146.4, 146.3, 145.3, 145.3, 144.8, 144.7, 143.7, 143.7, 143.6, 126.6, 126.5, 120.8, 120.8, 120.5, 120.4, 120.3, 120.3, 120.2, 120.1, 105.9, 105.7, 105.6, 49, 49, 45.8, 45.8, 45.5, 34.9, 34.9, 31.3, 31.2, 31.1, 29.3, 29.2, 27.4, 27.3, 25.9, 25.9, 25.9, 19.2, 18.5, 18.5, 12.1, 12.1.

Example 320: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.4, 2.8 Hz), 7.30 (1H, dd, J=8.9, 9.9 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.44 (2H, m), 3.40 (2H, m), 3.32 (3H, s), 2.86 (1H, dd, J=8.3, 4.2 Hz), 2.72 (2H, m), 2.65 (2H, m), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.5, 161.3, 159.6, 156.9, 130.6, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 64.9, 62.8, 52.4, 46.5, 45.8, 45.3, 42.5, 31.6, 31.5, 29, 22.1, 20.7, 15.2.

Example 321: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one hydrochloride

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one on the reaction with piperazine followed by salt formation in a mixture of ethyl acetate and 2M HCl in diethyl ether. The product was isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 9.30 (2H, m), 7.61-7.53 (2H, m), 7.24 (1H, dd, J=9.9, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.89 (2H, s), 3.86 (1H, d, J=12.2 Hz), 3.78 (2H, m), 3.70 (2H, m), 3.32 (3H, s), 3.17 (2H, m), 3.08 (2H, m), 2.85 (1H, dd, J=8.3, 4.2 Hz), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167, 161.8, 160.1, 157, 133.1, 133.1, 132.4, 132.3, 130.9, 129.1, 129, 118, 117.9, 116.2, 116.2, 115.7, 52.4, 42.6, 42.4, 42.1, 38.1, 31.6, 31.5, 28.8, 22.1, 20.7.

Example 322: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide (Example 273) and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 8.71 (1H, br s), 8.64 (1H, br s), 7.49 (1H, dd, J=6.4, 2.6 Hz), 7.45 (1H, m), 7.31 (1H, t, J=9.3 Hz), 4.15 (1H, d, J=12.2 Hz), 3.86 (1H, d, J=12.0 Hz), 3.55 (1H, m), 3.44 (3H, s), 3.18 (2H, br s), 3.03 (1H, dd, J=8.4, 4.3 Hz), 2.97 (2H, m), 1.99 (2H, m), 1.71 (3H, m), 1.62 (2H, td, J=12.8, 6.4 Hz), 1.56 (2H, m), 1.21 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.3, 159.6, 157.3, 130.9, 130.2, 130.2, 129.4, 129.4, 128.7, 128.6, 128.3, 128.3, 117.6, 117.5, 116.3, 58.2, 52.4, 43.8, 31.7, 31.3, 29.2, 29.1, 23.6, 22, 21, 20.6.

Example 323: (R)-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 8.17, 8.11 (1H, 2 s), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=9.7, 11.1 Hz), 4.11 (1H, s), 3.94 (1H, s), 3.84 (1H, dd, J=11.7, 7.7 Hz), 3.79 (2H, m), 3.66 (1H, m), 3.61 (1H, m), 3.36 (3H, 2 s), 3.32-3.25 (2H, m), 3.17 (1H, m), 2.90 (1H, br dd, J=15.8, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 166.7, 166.4, 165.8, 156.3, 156.3, 146.4, 146.4, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 128.1, 120.5, 120.4, 120.4, 120.3, 120.3, 120.2, 116.1, 116, 105.9, 105.7, 105.5, 49.4, 48.2, 45.7, 42.1, 38.4, 34.9, 34.9, 31.5, 29, 29.

Example 324: (R)-1-methyl-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 4.48 (1H, quin, J=8.1 Hz), 4.25 (1H, br t, J=10.3 Hz), 4.16 (1H, s), 4.00 (1H, s), 3.90-3.73 (4H, m), 3.69 (1H, m), 3.41 (1H, m), 3.39-3.34 (3H, m), 3.32-3.25 (2H, m), 2.90 (1H, m), 2.86 (3H, s).

¹³C NMR (DMSO_(d6)): 166.6, 166.5, 164.6, 164, 156.3, 156.3, 146.4, 146.4, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.1, 120.5, 120.4, 120.3, 116.1, 116, 105.9, 105.7, 105.5, 49.4, 48.4, 47.5, 47, 45.8, 42.1, 38.3, 34.9, 33.7, 33.5, 31.5, 29, 29, 28.8.

Example 325: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide

Compound was prepared analogous manner to Example 25 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one using DIPEA as base and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.98 (1H, d, J=7.8 Hz), 7.90-7.53 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.54 (1H, d, J=4.4 Hz), 4.14 (1H, d, J=12.0 Hz), 3.84 (1H, d, J=12.0 Hz), 3.47 (3H, m), 3.37 (1H, m), 3.34 (3H, s), 2.87 (1H, dd, J=8.4, 4.3 Hz), 1.79 (4H, m), 1.69 (1H, dd, J=8.4, 5.4 Hz), 1.19 (4H, m), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 161.8, 160.1, 156.8, 133.1, 133, 132.3, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 68.1, 62.8, 52.4, 47.5, 33.9, 31.5, 31.4, 31.3, 30.2, 30.1, 22, 20.7.

Example 326: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.44 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.82 (2H, m), 3.58 (4H, m), 3.32 (3H, s), 2.85 (1H, dd, J=8.3, 4.2 Hz), 2.65-2.36 (4H, m br), 2.30 (3H, br s), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.6, 161.3, 159.6, 156.9, 130.7, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116, 54.3, 53.9, 52.4, 45.1, 44.6, 40.8, 31.6, 31.5, 29, 22.1, 20.7.

Example 327: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(2-methyl-3-thioxo-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.11 (1H, br d, J=7.3 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.4 Hz), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.3, 9.4 Hz), 3.80 (1H, dd, J=11.5, 7.8 Hz), 3.65 (3H, m), 3.44 (2H, m), 3.39 (3H, s), 3.33 (1H, m), 3.29 (1H, m), 3.11 (1H, m), 2.88 (1H, dd, J=15.8, 8.1 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

¹³C NMR (DMSO_(d6)): 167.3, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.7, 118.6, 116.4, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 70.1, 67, 49.5, 45.1, 34.7, 31.5, 31.2, 29.2, 28.5, 23.8

Example 328: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.74 (1H, br t, J=5.7 Hz), 8.59 (1H, s), 8.55 (1H, dd, J=2.4, 1.5 Hz), 8.51 (1H, d, J=2.5 Hz), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.4 Hz), 4.43 (3H, m), 4.22 (1H, m), 3.80 (1H, dd, J=11.5, 8.0 Hz), 3.56 (2H, d, J=5.9 Hz), 3.40 (3H, m), 3.25 (1H, dd, J=15.8, 9.3 Hz), 2.85 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 168.2, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 153.9, 143.9, 143.5, 143.2, 129.7, 129.7, 128.6, 118.6, 118.5, 118.4, 116.1, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 49.4, 42.4, 34.7, 31.4, 31.2, 29.1.

Example 329: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.4 Hz), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, m), 3.80 (1H, dd, J=11.5, 7.7 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, m), 3.27 (1H, dd, J=15.9, 9.3 Hz), 2.86 (1H, dd, J=15.9, 7.8 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.2, 118.9, 118.8, 118.6, 116.2, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 66, 66, 49.5, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 330: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide (Example 272) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.77 (2H, m), 7.61 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.25 (1H, dd, J=10.1, 8.8 Hz), 4.14 (1H, d, J=11.9 Hz), 3.85 (1H, d, J=12.0 Hz), 3.54 (1H, m), 3.43 (3H, s), 3.17 (2H, br s), 3.04 (1H, dd, J=8.4, 4.3 Hz), 2.98 (2H, m), 1.99 (2H, m), 1.71 (3H, m), 1.63 (2H, m), 1.55 (2H, m), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.2, 157.2, 133.1, 133, 132.4, 132.4, 130.9, 129.2, 129.1, 118, 117.9, 116.3, 116.2, 58.2, 52.4, 43.8, 31.7, 31.3, 29.2, 29.1, 23.7, 22, 21, 20.6.

Example 331: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydro-2H-pyran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide (Example 277) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 9.05 (2H, m), 7.61 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.1, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 3.90 (1H, dd, J=11.6, 2.6 Hz), 3.85 (1H, d, J=12.0 Hz), 3.66 (1H, m), 3.59 (1H, dd, J=11.7, 7.1 Hz), 3.49 (1H, ddd, J=11.2, 8.2, 2.9 Hz), 3.43 (3H, s), 3.22 (3H, m), 3.03 (3H, m), 2.07 (1H, td, J=8.9, 4.4 Hz), 1.77 (2H, m), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.52 (1H, m), 1.19 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.2, 157.2, 133, 133, 132.4, 132.4, 130.7, 129.2, 129.1, 118, 117.9, 116.4, 116.2, 116.2, 67.3, 66.7, 52.4, 52.4, 42.4, 31.7, 31.4, 24.7, 22.4, 22.1, 20.9, 20.6.

Example 332: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light green solid.

¹H NMR (DMSO_(d6)): 8.99 (1H, br t, J=5.6 Hz), 8.74 (1H, br d, J=5.3 Hz), 8.32 (1H, br t, J=7.5 Hz), 7.75 (2H, m), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.44 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.31 (1H, dd, J=9.8, 8.9 Hz), 4.61 (2H, br d, J=5.6 Hz), 4.15 (1H, br d, J=11.9 Hz), 3.86 (1H, br d, J=12.0 Hz), 3.71 (2H, br m), 3.36 (3H, s), 2.94 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.4 Hz), 1.16 (1H, m).

¹³C NMR (DMSO_(d6)): 168.8, 161.2, 159.6, 156.8, 155.5, 143.7, 143.3, 131.4, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 124.4, 124, 117.6, 117.4, 115.7, 52.5, 41.7, 31.6, 31.5, 30.9, 22.1, 20.7.

Example 333: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.84 (1H, d, J=6.6 Hz), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.4 Hz), 4.78 (1H, m), 4.70 (2H, m), 4.42 (3H, m), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.80 (1H, dd, J=11.7, 7.7 Hz), 3.47 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.4 Hz), 2.90 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 129.7, 129.6, 128.6, 118.7, 118.6, 118.5, 116.1, 116, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 77, 76.9, 49.5, 44.2, 34.7, 31.5, 31, 29.1.

Example 334: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Example 298) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 10.19 (2H, m), 7.61 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.1, 8.8 Hz), 4.14 (1H, br d, J=11.9 Hz), 4.09 (2H, m), 3.84 (1H, d, J=12.0 Hz), 3.42 (3H, s), 3.27 (2H, br d, J=7.5 Hz), 3.08 (2H, m), 2.99 (1H, dd, J=8.3, 4.2 Hz), 1.69 (1H, dd, J=8.4, 5.4 Hz), 1.20 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 161.8, 160.1, 157.2, 133, 133, 132.4, 132.4, 130.8, 129.1, 129, 126.1, 124.3, 122.4, 120.6, 118, 117.8, 116.4, 116.2, 116.2, 52.4, 46.7, 46.5, 46.2, 46, 45.9, 31.6, 31.3, 22, 20.8, 20.6.

Example 335: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an orange solid.

¹H NMR (DMSO_(d6)): 8.79 (1H, t, J=5.7 Hz), 8.61 (1H, d, J=1.3 Hz), 8.58 (1H, dd, J=2.4, 1.5 Hz), 8.53 (1H, d, J=2.6 Hz), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.44 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.8, 8.9 Hz), 4.46 (2H, m), 4.16 (1H, br d, J=12.2 Hz), 3.87 (1H, d, J=12.0 Hz), 3.66 (2H, m), 3.37 (3H, s), 2.92 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.3, 5.4 Hz), 1.17 (1H, m).

¹³C NMR (DMSO_(d6)): 168.2, 161.2, 159.6, 153.9, 144, 143.9, 143.4, 143.2, 131.8, 130.2, 130.2, 129.4, 129.4, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 52.5, 42.4, 31.6, 31.5, 31, 22.1, 20.7.

Example 336: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.18 (1H, br t, J=5.6 Hz), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.4 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.22 (1H, m), 3.81 (2H, m), 3.72 (1H, m), 3.58 (1H, m), 3.45 (2H, m), 3.40 (3H, s), 3.28 (1H, dd, J=15.8, 9.3 Hz), 3.17 (1H, m), 3.08 (1H, m), 2.89 (1H, dd, J=15.8, 8.1 Hz), 1.85 (1H, m), 1.78 (2H, m), 1.46 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.6, 118.5, 116.4, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 77, 67.1, 49.4, 42.9, 34.7, 31.4, 31.2, 29.1, 28.4, 25.1.

Example 337: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.18 (1H, br t, J=5.6 Hz), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, m), 4.43 (1H, quin, J=8.5 Hz), 4.22 (1H, m), 3.81 (2H, m), 3.72 (1H, m), 3.58 (1H, m), 3.45 (2H, m), 3.40 (3H, s), 3.28 (1H, dd, J=15.8, 9.4 Hz), 3.16 (1H, m), 3.10 (1H, m), 2.89 (1H, dd, J=15.8, 8.1 Hz), 1.85 (1H, m), 1.78 (2H, m), 1.46 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.6, 118.5, 116.4, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 77, 67.1, 49.5, 42.9, 34.7, 31.4, 31.2, 29.1, 28.4, 25.1.

Example 338: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.36 (1H, t, J=5.5 Hz), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.54 (1H, s), 7.29 (1H, s), 7.22 (1H, m), 4.42 (1H, quin, J=8.6 Hz), 4.22 (1H, m), 4.08 (2H, m), 3.80 (1H, dd, J=11.5, 8.0 Hz), 3.75 (3H, s), 3.44 (2H, m), 3.38 (3H, s), 3.23 (1H, dd, J=15.8, 9.3 Hz), 2.85 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 167.3, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 137.9, 129.7, 129.7, 129.4, 128.4, 118.7, 118.5, 118.4, 116.4, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 49.4, 38.3, 34.7, 33.2, 31.4, 31.2, 29.1.

Example 339: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.39 (1H, br t, J=5.5 Hz), 7.56 (1H, s), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.31 (2H, m), 4.12 (3H, m), 3.85 (1H, d, J=12.0 Hz), 3.77 (3H, s), 3.52 (2H, m), 3.33 (3H, m), 2.87 (1H, dd, J=8.4, 4.1 Hz), 1.67 (1H, dd, J=8.3, 5.4 Hz), 1.15 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 161.3, 159.6, 156.9, 137.9, 131.1, 130.2, 130.2, 129.4, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 118.5, 117.6, 117.4, 116, 52.4, 38.4, 33.2, 31.5, 31.4, 31.1, 22, 20.7.

Example 340: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.39 (1H, s), 7.85 (1H, m), 7.48 (1H, d, J=3.5 Hz), 7.23 (1H, d, J=3.5 Hz), 4.50 (1H, quin, J=8.5 Hz), 4.26 (1H, dd, J=11.4, 9.3 Hz), 3.86 (1H, dd, J=7.7, 11.4 Hz), 3.84 (2H, m), 3.43 (3H, s), 3.36 (1H, m), 2.96 (1H, dd, J=16.0, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 167, 157.8, 156.6, 146.4, 146.4, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 137.7, 129, 120.4, 120.3, 120.2, 115.1, 113.8, 105.9, 105.7, 105.6, 49.5, 34.8, 31.6, 30.8, 29.1.

Example 341: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclohexylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide (Example 294) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.69 (2H, m), 7.61 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.43 (3H, s), 3.20 (2H, m), 3.01 (4H, m), 2.06 (2H, m), 1.77 (2H, m), 1.70 (1H, dd, J=8.2, 5.3 Hz), 1.61 (1H, m), 1.27 (4H, m), 1.19 (1H, t, J=4.8 Hz), 1.12 (1H, m).

¹³C NMR (DMSO_(d6)): 161.8, 160.2, 157.2, 133.1, 132.4, 132.4, 130.8, 129.1, 129, 118, 117.9, 116.4, 116.2, 116.2, 55.8, 52.4, 41.6, 31.7, 31.3, 28.7, 28.5, 24.7, 23.9, 23.9, 22, 21, 20.6.

Example 342: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-2-oxopyrrolidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, d, J=8.1 Hz), 7.84 (1H, s), 7.72 (1H, m), 7.16 (1H, t, J=9.2 Hz), 4.43 (1H, quin, J=8.4 Hz), 4.28 (1H, m), 4.22 (1H, br t, J=10.3 Hz), 3.80 (1H, dd, J=11.4, 8.1 Hz), 3.47 (2H, s), 3.42 (3H, s), 3.16 (2H, m), 2.89 (1H, br dd, J=15.8, 8.3 Hz), 2.29 (1H, m), 1.81 (1H, m).

¹³C NMR (DMSO_(d6)): 174.2, 167.8, 160.9, 160.8, 159.2, 159.2, 157.6, 157.5, 156.2, 156, 155.9, 132.5, 132.5, 128.6, 118.6, 118.5, 118.4, 116.2, 113.8, 113.8, 113.7, 113.6, 104.1, 104.1, 103.9, 103.9, 49.9, 49.5, 38, 34.8, 31.4, 31.3, 29.1, 28.2.

Example 343: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-((pyridin-2-ylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide hydrochloride (Example 332) and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 9.45 (2H, br s), 8.66 (1H, br d, J=4.7 Hz), 7.92 (1H, td, J=7.7, 1.5 Hz), 7.57 (1H, d, J=7.8 Hz), 7.47 (3H, m), 7.32 (1H, t, J=9.3 Hz), 4.39 (2H, br s), 4.15 (1H, br d, J=11.9 Hz), 3.86 (1H, m), 3.43 (3H, s), 3.29 (2H, m), 3.07 (3H, m), 1.69 (1H, dd, J=8.1, 5.4 Hz), 1.21 (1H, br t, J=4.6 Hz).

¹³C NMR (DMSO_(d6)): 161.3, 159.6, 157.4, 151.9, 148.9, 137.6, 131.1, 130.2, 130.2, 129.5, 129.4, 128.7, 128.6, 128.3, 128.3, 123.8, 123.3, 117.6, 117.4, 116.3, 52.4, 50.1, 44.9, 31.7, 31.4, 22.1, 20.8, 20.6.

Example 344: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 5.04 (0.2H, quin, J=7.8 Hz), 4.76 (0.8H, quin, J=8.2 Hz), 4.45 (1H, m), 4.24 (1H, dd, J=9.5, 11.3 Hz), 3.82 (1H, dd, J=7.7, 11.5 Hz), 3.79 (2H, m), 3.64 (2H, m), 3.35 (3H, m), 3.30 (1H, dd, J=15.8, 9.7 Hz), 2.89 (1H, br dd, J=15.8, 8.1 Hz), 2.15-1.84 (4H, m).

¹³C NMR (DMSO_(d6)): 168.6, 168.1, 156.9, 156.9, 156.9, 156.4, 156.3, 155.3, 155.3, 155.3, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 145.9, 145.9, 145.9, 145.8, 128.6, 127, 125.1, 119, 118.9, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116, 115.8, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 57.5, 57.3, 56.7, 56.5, 56.3, 56.1, 49.5, 46.9, 34.7, 31.5, 31.4, 30.5, 29.5, 29.2, 29.1, 26.2, 24.8, 23.6, 21.3.

Example 345: N-(2-cyanocyclopentyl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.55 (0.5H, d, J=7.6 Hz), 8.39 (0.5H, dd, J=7.6, 2.4 Hz), 7.47 (1H, m), 7.18 (1H, m), 4.43 (1H, m), 4.24 (2H, m), 3.82 (1H, m), 3.52 (1H, m), 3.47 (1H, s), 3.42, 3.40 (3H, 2 s), 3.32-3.23 (1.5H, m), 2.93 (1H, m), 2.83 (0.5H, m), 2.15-2.0 (1H, m), 1.99-1.88 (1H, m), 1.89-1.74 (1.5H, m), 1.74-1.64 (1H, m), 1.62-1.52 (1H, m), 1.47 (0.5H, m).

¹³C NMR (DMSO_(d6)): 167.8, 167.7, 157, 156.9, 156.3, 156.2, 156.2, 155.4, 155.3, 155.3, 149.1, 149.1, 149, 147.6, 147.5, 147.5, 147.3, 145.9, 145.9, 145.9, 145.8, 128.5, 122, 120.7, 120.7, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116.3, 116.3, 116.1, 116.1, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 54.4, 54.4, 51.4, 49.4, 34.7, 33.9, 33.9, 33.7, 33.7, 31.5, 31.4, 31.3, 31.2, 30.9, 30.9, 30.1, 29.1, 29.1, 28.8, 28.6, 28.6, 22.3, 22.3, 22.1.

Example 346: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide (Example 339) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 9.25 (2H, m), 7.84 (1H, s), 7.58 (1H, s), 7.50 (1H, dd, J=6.5, 2.6 Hz), 7.44 (1H, m), 7.31 (1H, t, J=9.4 Hz), 4.14 (1H, br d, J=12.0 Hz), 4.05 (2H, br t, J=5.5 Hz), 3.84 (4H, m), 3.42 (3H, s), 3.15 (2H, m), 3.03 (3H, m), 1.67 (1H, dd, J=8.2, 5.4 Hz), 1.20 (1H, t, J=4.7 Hz).

¹³C NMR (DMSO_(d6)): 159.6, 157.2, 139.7, 131.8, 130.9, 130.2, 130.2, 129.4, 129.4, 128.7, 128.6, 128.3, 117.6, 117.4, 116.5, 111.2, 52.4, 43.9, 40.5, 38.6, 31.7, 31.4, 22.8, 22.1, 20.7.

Example 347: (R)-N-(isoxazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 10.49 (1H, s), 9.11 (1H, s), 8.63 (1H, s), 7.47 (1H, m), 7.18 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.25 (1H, dd, J=9.6, 11.2 Hz), 3.83 (1H, dd, J=11.4, 8.1 Hz), 3.71 (2H, m), 3.43 (3H, s), 3.32 (1H, dd, J=9.3, 16.1 Hz), 2.94 (1H, dd, J=15.9, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 166.3, 159.2, 157, 157, 156.9, 156.9, 156.5, 155.3, 155.3, 149.1, 149, 149, 149, 147.5, 147.5, 147.5, 147.4, 147.4, 147.2, 145.9, 145.9, 145.9, 145.8, 144.3, 144.3, 128.9, 119.6, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.5, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 34.7, 31.6, 31.1, 29.1.

Example 348: (S)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, t, J=9.6 Hz), 4.45 (1H, quin, J=8.6 Hz), 4.24 (1H, dd, J=9.5, 11.3 Hz), 3.88-3.40 (8H, several mult.), 3.37 (3H, s), 3.29 (1H, dd, J=9.2, 15.8 Hz), 2.90 (1H, m), 2.32 (0.5H, m), 2.21 (1H, m), 2.10 (0.5H, m).

¹³C NMR (DMSO_(d6)): 166.6, 166.4, 156.9, 156.9, 156.9, 156.9, 156.3, 155.3, 155.3, 149.1, 149, 149, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 145.8, 128.4, 121.1, 120.9, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 115.9, 115.9, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 49.5, 48.7, 48.6, 44.8, 44.6, 34.7, 31.5, 30.2, 30.1, 29.6, 29.1, 28.1, 28, 26.5.

Example 349: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.78 (1H, m), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.3, 9.4 Hz), 3.82 (3H, br dd, J=11.4, 7.7 Hz), 3.41 (3H, m), 3.33 (1H, m), 2.93 (1H, dd, J=15.9, 8.0 Hz), 2.43 (3H, s).

¹³C NMR (DMSO_(d6)): 166.8, 160.5, 160.1, 160.1, 158.5, 158.4, 157, 156.6, 156.5, 154.9, 154.9, 129.7, 129.7, 129.3, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 114.8, 113.2, 113.2, 113.1, 113.1, 49.6, 34.7, 31.6, 31.5, 29.2, 10.6.

Example 350: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 10.16 (1H, s), 7.85 (1H, s), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.39 (1H, s), 7.21 (1H, t, J=9.4 Hz), 4.45 (1H, quin, J=8.5 Hz), 4.23 (1H, m), 3.81 (1H, br dd, J=11.4, 7.9 Hz), 3.77 (3H, s), 3.62 (2H, m), 3.42 (3H, s), 3.29 (1H, m), 2.90 (1H, br dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 165, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 129.7, 129.7, 129.6, 128.7, 128.6, 121.4, 121.2, 118.7, 118.6, 118.5, 116.1, 113.3, 113.2, 113.1, 113.1, 49.5, 38.6, 34.7, 31.5, 31.3, 29.1.

Example 351: (R)-N-(isothiazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 10.87 (1H, s), 8.88 (1H, s), 8.59 (1H, s), 7.47 (1H, m), 7.18 (1H, m), 4.45 (1H, quin, J=8.7 Hz), 4.25 (1H, dd, J=9.5, 11.4 Hz), 3.83 (1H, dd, J=11.5, 8.0 Hz), 3.72 (2H, m), 3.44 (3H, s), 3.33 (1H, dd, J=9.5, 15.8 Hz), 2.94 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 166.2, 157, 157, 156.9, 156.5, 155.3, 155.3, 155.3, 150.8, 149.1, 149, 149, 149, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 145.8, 134.7, 132.6, 128.8, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.7, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 34.7, 31.6, 31.4, 29.1.

Example 352: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.09 (1H, br t, J=5.7 Hz), 7.62 (1H, td, J=8.8, 5.6 Hz), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, m), 3.81 (3H, m), 3.44 (2H, m), 3.40 (3H, s), 3.29 (1H, m), 3.22 (2H, tt, J=11.7, 2.3 Hz), 2.96 (2H, m), 2.88 (1H, dd, J=15.8, 8.1 Hz), 1.62 (1H, m), 1.51 (2H, br d, J=12.6 Hz), 1.13 (2H, m).

¹³C NMR (DMSO_(d6)): 167.8, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.7, 128.4, 118.8, 118.7, 118.5, 116.5, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 66.7, 49.5, 44.5, 34.7, 34.7, 31.5, 31.2, 30.3, 29.2.

Example 353: 1-(3-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 4.54-4.34 (3H, m), 4.24 (1H, dd, J=9.6, 11.0 Hz), 3.81 (1H, dd, J=11.6, 7.9 Hz), 3.75-3.58 (3H, m), 3.55-3.44 (1.5H, m), 3.37 (3H, m), 3.29 (2H, m), 3.12 (0.5H, m), 2.88 (1H, m), 2.67 (0.5H, m), 2.53 (0.5H, m), 2.05 (0.5H, m), 1.94 (0.5H, m), 1.77 (0.5H, m), 1.64 (0.5H, m).

¹³C NMR (DMSO_(d6)): 166.3, 166.2, 157, 156.9, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 128.2, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.2, 111.9, 111.8, 84.8, 84.8, 83.7, 83.7, 49.4, 48, 47.9, 47.9, 47.9, 47.2, 47.2, 47.2, 47.2, 45.4, 45, 37.3, 37.2, 37.1, 37.1, 34.7, 31.5, 30.3, 30.1, 30.1, 29.1, 27.2, 27.1, 25.4, 25.4, 25.4, 25.3.

Example 354: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-2-oxopiperidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (R)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.30 (1H, d, J=8.3 Hz), 7.62 (1H, br s), 7.47 (1H, m), 7.18 (1H, m), 4.42 (1H, m), 4.23 (1H, dd, J=9.6, 11.3 Hz), 4.13 (1H, m), 3.81 (1H, dd, J=11.4, 8.1 Hz), 3.47 (2H, m), 3.42 (3H, s), 3.29 (1H, dd, J=15.7, 9.3 Hz), 3.11 (2H, m), 2.95 (1H, dd, J=16.0, 8.3 Hz), 1.94 (1H, m), 1.81-1.66 (2H, m), 1.60 (1H, m).

¹³C NMR (DMSO_(d6)): 169.5, 167.4, 157, 156.9, 156.9, 156.2, 155.4, 155.3, 155.3, 149.1, 149.1, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 145.9, 145.8, 128.6, 128.5, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 49.4, 49.2, 41, 34.7, 31.4, 31.3, 29.1, 27.5, 21.

Example 355: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide

Compound was prepared analogous manner to Example 25 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one using DIPEA as base and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 7.44 (1H, dd, J=6.5, 2.6 Hz), 7.35 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.16 (1H, dd, J=9.8, 8.9 Hz), 4.24 (1H, d, J=12.3 Hz), 3.97 (1H, d, J=12.2 Hz), 3.65 (1H, m), 3.56 (2H, s), 3.52 (1H, m), 3.48 (3H, s), 2.81 (1H, dd, J=8.3, 4.0 Hz), 1.95 (4H, m), 1.68 (1H, dd, J=8.4, 5.6 Hz), 1.34 (4H, m), 1.18 (1H, m).

¹³C NMR (DMSO_(d6)): 170.2, 163.3, 161.6, 157.7, 133.8, 131.5, 131.5, 130.9, 130.8, 130.7, 130.7, 130, 129.9, 118.5, 118.4, 118, 70.5, 54.3, 54.3, 49.3, 34.9, 33.3, 32.5, 32.4, 31.6, 23.3, 22.3.

Example 356: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.98 (1H, br d, J=7.8 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=9.0 Hz), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, m), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.51 (1H, m), 3.39 (3H, m), 3.28 (1H, br dd, J=15.9, 9.3 Hz), 2.88 (1H, br dd, J=15.8, 7.9 Hz), 1.80-1.40 (6H, m), 1.32-0.97 (6H, m).

¹³C NMR (DMSO_(d6)): 166.5, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.1, 154.9, 154.9, 129.7, 129.6, 128.3, 118.9, 118.7, 118.6, 116.6, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 49.5, 47.7, 34.7, 33.3, 32.3, 31.4, 31.3, 29.2, 25.2, 24.5.

Example 357: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.19 (1H, d, J=4.0 Hz), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.46 (2H, m), 3.34 (3H, s), 2.89 (1H, dd, J=8.4, 4.1 Hz), 2.64 (1H, m), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.14 (1H, t, J=4.8 Hz), 0.63 (2H, m), 0.42 (2H, m).

¹³C NMR (DMSO_(d6)): 168.9, 161.8, 160.1, 156.8, 133, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 116, 52.4, 52.4, 31.5, 31.4, 31, 22.5, 22.1, 20.7, 5.6.

Example 358: N,N-dimethyl-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carboxamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 4.43 (1H, m), 4.24 (1H, dd, J=9.5, 11.2 Hz), 3.81 (1H, dd, J=11.4, 8.1 Hz), 3.75-3.42 (5.5H, several. mult.), 3.38 (3H, s), 3.37 (1H, m), 3.29 (1.5H, m), 3.03, 3.02 (3H, 3 s), 2.89 (1H, m), 2.82 (3H, 4 s), 2.12 (0.5H, m), 2.05 (0.5H, m), 1.97 (0.5H, m), 1.85 (0.5H, m).

¹³C NMR (DMSO_(d6)): 171.7, 171.7, 171.3, 171.3, 166.1, 166, 166, 166, 156.9, 156.9, 156.2, 156.2, 155.3, 155.3, 155.3, 149.1, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.2, 119, 118.9, 118.9, 118.8, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.3, 116.2, 116.2, 116.2, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 49.4, 48.6, 48.4, 45.8, 45.8, 45.3, 45.2, 40.2, 40, 38.3, 36.7, 35.1, 35.1, 35, 34.7, 34.7, 31.5, 30.3, 30.3, 30.2, 29.1, 29.1, 29, 27.5.

Example 359: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide (Example 279) and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.50 (1H, m), 7.11 (1H, t, J=9.4 Hz), 4.23 (1H, d, J=12.2 Hz), 3.95 (2H, m), 3.83 (1H, dd, J=9.2, 5.9 Hz), 3.76 (1H, td, J=8.3, 6.4 Hz), 3.65 (1H, dd, J=9.2, 4.0 Hz), 3.52 (4H, s), 3.04-2.77 (5H, m), 2.19 (1H, td, J=13.4, 7.6 Hz), 1.81 (1H, m), 1.70 (1H, dd, J=8.2, 5.6 Hz), 1.16 (1H, m).

¹³C NMR (DMSO_(d6)): 163.8, 162.2, 157.5, 134.5, 134.5, 134, 133.9, 132.7, 130.5, 130.4, 121, 119, 118.8, 118, 118, 73.5, 68.3, 59.7, 54.2, 54.1, 47.1, 33.3, 33.2, 32.2, 25.4, 23.3, 22.4.

Example 360: 2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a khaki powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, s), 8.23 (1H, d, J=6.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.21 (1H, m), 4.17 (1H, dd, J=11.6, 9.1 Hz), 3.77 (2H, m), 3.71 (1H, dd, J=8.9, 5.9 Hz), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.25 (1H, m), 3.25 (2H, s), 2.88 (1H, dd, J=15.8, 8.3 Hz), 2.06 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.5, 120.3, 120.2, 114.3, 105.9, 105.7, 105.6, 72.4, 66.3, 49.8, 48.4, 35.7, 32, 31.3, 29.2.

Example 361: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 11.65 (1H, br s), 7.56 (2H, m), 7.24 (1H, t, J=9.3 Hz), 4.08 (1H, br d, J=11.9 Hz), 3.79 (1H, d, J=12.2 Hz), 3.42 (2H, m), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.66 (1H, dd, J=8.1, 5.4 Hz), 1.10 (1H, m).

¹³C NMR (DMSO_(d6)): 171.1, 161.8, 160.1, 155.9, 132.9, 132.9, 132.3, 132.3, 131.8, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.7, 51.6, 51.6, 32.3, 30.5, 22.2, 20.6.

Example 362: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.22 (1H, br d, J=6.6 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=8.9 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.21 (1H, m), 4.15 (1H, dd, J=11.2, 9.5 Hz), 3.73 (3H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.21 (1H, dd, J=9.0, 15.6 Hz), 2.84 (1H, dd, J=15.6, 8.1 Hz), 2.06 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 129.1, 118.8, 118.7, 118.5, 116, 116, 115.9, 115.9, 114.2, 113.2, 113.2, 113.1, 113.1, 72.4, 72.4, 66.3, 49.7, 48.5, 35.6, 32, 31.9, 31.3, 29.3.

Example 363: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, br s), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, t, J=8.9 Hz), 4.45 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.1, 9.6 Hz), 3.73 (1H, dd, J=11.4, 7.9 Hz), 3.55 (4H, m), 3.51 (2H, s), 3.44 (4H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.83 (1H, dd, J=15.7, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.6, 129.3, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114, 113.2, 113.2, 113.1, 113.1, 66, 66, 48.6, 45.7, 41.7, 35.6, 29.3, 28.8.

Example 364: N-methyl-N-(tetrahydrofuran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, m), 7.47 (1H, qd, J=9.4, 5.1 Hz), 7.18 (1H, t, J=9.5 Hz), 5.08 (0.6H, m), 4.61 (0.4H, m), 4.43 (1H, quin, J=8.6 Hz), 4.16 (1H, m), 3.92 (1H, m), 3.74 (1H, dd, J=11.5, 8.0 Hz), 3.67 (0.8H, m), 3.64-3.53 (3H, m), 3.48 (1.2H, s), 3.21 (1H, m), 2.88 (1.8H, s), 2.83 (1H, m), 2.72 (1.2H, s), 2.10 (1H, m), 1.78 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 157, 156.9, 156.9, 155.3, 155.3, 155.2, 155.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.2, 129.2, 119, 118.9, 118.8, 118.8, 118.7, 118.7, 116.5, 116.4, 116.4, 116.3, 114.3, 114.2, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 69.3, 69.3, 69.3, 67.1, 67.1, 56.5, 52.9, 48.5, 35.6, 30, 29.8, 29.8, 29.7, 29.5, 29.5, 29.3, 29.2, 29.2, 27.6.

Example 365: N-((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.96 (1H, br d, J=7.5 Hz), 7.47 (1H, qd, J=9.4, 5.1 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.16 (1H, m), 3.74 (1H, dd, J=11.5, 8.1 Hz), 3.65 (3H, m), 3.33 (1H, m), 3.25 (2H, s), 3.22 (1H, dd, J=16.0, 9.5 Hz), 3.09 (1H, m), 2.85 (1H, dd, J=15.7, 8.4 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.45 (2H, m).

¹³C NMR (DMSO_(d6)): 167.2, 157, 156.9, 155.3, 155.3, 155.1, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 114.4, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 70.2, 67, 48.5, 45.1, 35.6, 31.4, 29.3, 28.6, 23.9.

Example 366: (R)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.70 (1H, s), 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.17 (1H, dd, J=11.1, 9.5 Hz), 3.74 (1H, dd, J=11.6, 8.1 Hz), 3.55 (4H, m), 3.51 (2H, s), 3.45 (4H, m), 3.22 (1H, dd, J=15.7, 9.2 Hz), 2.85 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 157, 157, 156.9, 156.9, 155.4, 155.3, 155.3, 155.2, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.8, 129.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 114.1, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 66, 66, 48.5, 45.7, 41.7, 35.6, 29.2, 28.8.

Example 367: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.11 (1H, d, J=7.6 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.80 (3H, m), 3.75 (1H, m), 3.42 (2H, d, J=2.2 Hz), 3.40 (3H, s), 3.33 (2H, m), 3.29 (1H, dd, J=9.2, 15.8 Hz), 2.89 (1H, dd, J=15.8, 8.1 Hz), 1.69 (2H, dt, J=12.7, 2.2 Hz), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.7, 118.6, 116.5, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 65.8, 49.5, 45.2, 34.7, 32.4, 32.4, 31.5, 31.3, 29.2.

Example 368: 2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.22 (1H, d, J=6.6 Hz), 7.47 (1H, qd, J=9.5, 5.1 Hz), 7.18 (1H, tdd, J=9.6, 9.6, 3.7, 1.8 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.21 (1H, tt, J=10.2, 3.9 Hz), 4.16 (1H, dd, J=11.4, 9.3 Hz), 3.73 (3H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.6 Hz), 3.24 (2H, s), 3.22 (1H, m), 2.86 (1H, dd, J=15.8, 8.4 Hz), 2.06 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 157, 156.9, 156.9, 155.4, 155.3, 155.3, 155.1, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.1, 118.9, 118.8, 118.7, 118.7, 116.5, 116.4, 116.4, 116.3, 114.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 48.5, 35.6, 32, 31.3, 29.3.

Example 369: 2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a khaki powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, br s), 8.23 (1H, br d, J=6.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.21 (1H, m), 4.17 (1H, dd, J=11.7, 9.2 Hz), 3.77 (2H, m), 3.71 (1H, dd, J=8.9, 6.0 Hz), 3.65 (1H, td, J=8.3, 5.5 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.25 (2H, s), 3.25 (1H, dd, J=9.4, 15.8 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz), 2.06 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.8, 105.7, 105.5, 72.4, 66.3, 49.8, 48.4, 35.7, 31.9, 31.3, 29.2.

Example 370: 2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, br s), 8.22 (1H, br d, J=6.6 Hz), 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.21 (1H, m), 4.16 (1H, m), 3.82-3.69 (3H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.22 (1H, m), 2.86 (1H, dd, J=15.7, 8.5 Hz), 2.06 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 157, 157, 156.9, 156.9, 155.4, 155.3, 155.3, 155.1, 149.1, 149, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.1, 118.9, 118.8, 118.7, 118.7, 116.5, 116.4, 116.4, 116.3, 114.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 48.5, 35.6, 32, 31.3, 29.3.

Example 371: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (R)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.35 (1H, d, J=7.7 Hz), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.6 Hz), 4.24 (1H, dd, J=11.2, 9.4 Hz), 4.04 (1H, m), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.47 (2H, m), 3.40 (4H, m), 3.30 (1H, dd, J=9.3, 15.8 Hz), 3.07 (1H, ddd, J=12.1, 6.9, 2.2 Hz), 2.91 (1H, dd, J=15.8, 8.2 Hz), 2.77 (3H, 2 s), 2.28 (2H, m), 1.85 (1H, m), 1.75 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 157, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.8, 118.7, 116.5, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 52.9, 49.5, 43.4, 43.4, 34.7, 33.9, 31.5, 31.1, 31.1, 29.2, 29, 29, 26.1.

Example 372: (R)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.45 (1.6H, m), 4.24 (1H, br t, J=10.3 Hz), 3.90 (2.4H, m), 3.82 (1.8H, m), 3.72 (1.2H, m), 3.40 (1.8H, m), 3.30 (1.2H, m), 2.96-2.84 (2.8H, m), 2.72 (1.2H, s), 1.84-1.63 (2H, m), 1.58 (0.8H, m), 1.41 (1.2H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.5, 157, 156.9, 156.9, 156.9, 156.2, 156.2, 155.3, 155.3, 149.1, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 128.2, 128.2, 119, 118.9, 118.9, 118.8, 116.8, 116.6, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 66.5, 66.3, 53, 49.7, 49.4, 34.8, 31.5, 31.5, 30.2, 30.2, 29.9, 29.5, 29.2, 29.2, 29.2, 29, 27.1.

Example 373: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.45 (1.6H, m), 4.23 (1H, br t, J=10.3 Hz), 3.98-3.84 (2.4H, m), 3.84-3.76 (1.8H, m), 3.72 (1.2H, m), 3.43-3.23 (3H, m), 3.35 (3H, s), 2.89 (1.8H, s), 2.86 (1H, m), 2.72 (1.2H, s), 1.83-1.64 (2H, m), 1.58 (0.8H, br t, J=10.9 Hz), 1.40 (1.2H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.5, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.2, 128.2, 119, 118.9, 118.8, 118.8, 118.7, 118.7, 116.7, 116.5, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 66.5, 66.3, 53, 49.7, 49.5, 34.8, 31.5, 31.5, 30.2, 30.2, 29.9, 29.5, 29.2, 29.2, 29.2, 29.1, 27.1.

Example 374: N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.43 (1H, quin, J=8.6 Hz), 4.24 (1H, m), 3.92 (1H, m), 3.82 (1.8H, m), 3.71 (2H, s), 3.65-3.52 (2.2H, m), 3.27 (1H, m), 2.93 (1.8H, s), 2.87 (1H, m), 2.74 (1.2H, s), 2.20 (0.4H, m), 2.10 (0.6H, m), 1.85 (0.4H, m), 1.77 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 157, 156.9, 156.2, 156.2, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.2, 128.1, 118.9, 118.8, 118.8, 118.7, 116.6, 116.5, 116.4, 116.4, 116.3, 112, 111.8, 69.4, 69.4, 69.3, 69.2, 67.1, 67.1, 56.6, 56.5, 53, 49.4, 34.8, 31.5, 31.5, 30, 29.8, 29.7, 29.7, 29.4, 29.4, 29.3, 29.1, 29.1, 27.6.

Example 375: N-methyl-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a yellowish powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.48 (1H, quin, J=8.4 Hz), 4.25 (1H, dd, J=11.3, 9.4 Hz), 3.92 (1H, m), 3.84 (1.8H, m), 3.76-3.65 (2H, s), 3.62 (1.2H, m), 3.56 (1H, m), 3.35 (3H, 2 s), 3.29 (1H, m), 2.93 (1.8H, m), 2.89 (1H, m), 2.74 (1.2H, s), 2.20 (0.4H, m), 2.10 (0.6H, m), 1.86 (0.4H, m), 1.78 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 167.6, 156.2, 146.4, 146.4, 146.4, 146.4, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.1, 127.9, 120.5, 120.4, 120.3, 116.6, 116.5, 105.9, 105.7, 105.6, 69.4, 69.4, 69.3, 69.2, 67.1, 67, 56.6, 56.5, 53, 49.4, 34.9, 31.5, 31.5, 30, 29.8, 29.7, 29.7, 29.4, 29.4, 29.3, 29.1, 29, 27.6, 27.6.

Example 376: (R)-N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.98 (1H, br d, J=7.5 Hz), 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=11.2, 9.5 Hz), 3.80 (2H, dt, J=11.3, 3.3 Hz), 3.73 (2H, m), 3.31 (2H, m), 3.23 (2H, s), 3.22 (1H, dd, J=9.1, 15.5 Hz), 2.86 (1H, dd, J=15.8, 8.3 Hz), 1.68 (2H, m), 1.37 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 157, 156.9, 155.4, 155.3, 155.1, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.5, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 129, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 114.4, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 65.8, 48.5, 45.2, 35.6, 32.4, 31.5, 29.4.

Example 377: (R)-N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as beige powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, s), 7.98 (1H, br d, J=7.5 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.3 Hz), 3.89-3.67 (4H, m), 3.32 (2H, m), 3.25 (1H, dd, J=9.2, 16.1 Hz), 3.24 (2H, s), 2.88 (1H, dd, J=8.1, 15.8 Hz), 1.67 (2H, m), 1.37 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 155.1, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 145.4, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.5, 120.4, 120.3, 114.4, 105.9, 105.7, 105.6, 65.8, 48.4, 45.2, 35.7, 32.4, 31.5, 29.3.

Example 378: (R)-N-methyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.71 (1H, br s), 7.85 (1H, m), 4.47 (1.6H, m), 4.18 (1H, br t, J=10.3 Hz), 3.88 (2.4H, m), 3.78 (1H, m), 3.58, 3.49 (2H, 2 s), 3.33 (2H, m), 3.25 (1H, m), 2.84 (2.8H, s), 2.70 (1.2H, s), 1.85-1.62 (2H, m), 1.51 (0.8H, m), 1.38 (1.2H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 155.1, 146.5, 146.4, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.9, 144.8, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129.1, 129, 120.5, 114.5, 114.3, 105.9, 105.7, 105.5, 66.5, 66.3, 53, 49.6, 48.5, 35.8, 30.3, 30.2, 30, 29.6, 29.3, 29.2, 29.2, 27.

Example 379: (R)-N-methyl-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.69 (1H, s), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.44 (1.6H, m), 4.17 (1H, br t, J=10.3 Hz), 3.88 (2.4H, m), 3.74 (1H, dd, J=11.3, 8.2 Hz), 3.57 (0.8H, m), 3.49 (1.2H, m), 3.40-3.30 (2H, m), 3.22 (1H, m), 2.84 (2.8H, m), 2.70 (1.2H, s), 1.83-1.62 (2H, m), 1.52 (0.8H, m), 1.37 (1.2H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 156.9, 156.9, 155.3, 155.3, 155.1, 155.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 129.2, 129.2, 119, 119, 118.9, 118.9, 118.9, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.3, 114.5, 114.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 66.5, 66.2, 53, 49.6, 48.5, 35.6, 30.3, 30.2, 30, 29.6, 29.4, 29.2, 27.

Example 380: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, br s), 7.61 (1H, td, J=8.6, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.45 (1.6H, m), 4.16 (1H, br t, J=10.3 Hz), 3.88 (2.4H, m), 3.73 (1H, dd, J=11.4, 8.0 Hz), 3.57 (1.2H, m), 3.49 (1.8H, m), 3.39 (1H, m), 3.34 (1H, m), 3.31 (1H, dd, J=4.5, 2.2 Hz), 3.22 (1H, m), 2.84 (2H, s), 2.70 (1H, s), 1.71 (2H, m), 1.52 (1H, br t, J=12.5 Hz), 1.37 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.1, 155, 154.9, 154.9, 129.7, 129.6, 129.3, 129.2, 119, 118.9, 118.8, 118.8, 118.7, 118.7, 116.1, 116, 115.9, 115.9, 114.4, 114.2, 113.3, 113.2, 113.1, 113.1, 66.5, 66.5, 66.2, 53, 49.6, 48.6, 35.6, 30.3, 30.2, 30, 29.6, 29.4, 29.2, 29.2, 27.

Example 381: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.63 (1H, br d, J=13.5 Hz), 7.63 (1H, m), 7.20 (1H, br t, J=9.2 Hz), 4.49 (0.6H, m), 4.18-3.92 (1.8H, m), 3.89 (2H, m), 3.72 (0.6H, m), 3.70-3.48 (2H, m), 3.45-3.30 (2H, m), 2.90-2.63 (4H, m), 1.84-1.15 (6H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 161.2, 159.6, 157.8, 157.7, 156.1, 156.1, 155.9, 155.8, 131.5, 131.3, 130.3, 130.3, 130.3, 130.3, 130.2, 117.1, 116.9, 115.7, 115.7, 115.6, 115.6, 114.5, 114.2, 112.9, 112.9, 112.8, 66.5, 66.5, 66.3, 64.9, 52.9, 51.4, 51.4, 49.6, 49.4, 30.2, 29.6, 29.3, 29.2, 29.2, 27.1, 26.5, 26.4, 21.8, 21.7, 21.3, 21.2.

Example 382: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(2-methyl-3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.11 (1H, br d, J=7.5 Hz), 7.72 (1H, td, J=8.5, 5.8 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, m), 3.79 (1H, dd, J=11.6, 7.6 Hz), 3.65 (3H, m), 3.44 (2H, m), 3.39 (3H, s), 3.33 (1H, m), 3.28 (1H, dd, J=15.8, 9.4 Hz), 3.11 (1H, m), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

¹³C NMR (DMSO_(d6)): 167.3, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.1, 155.9, 155.9, 132.5, 132.4, 128.4, 118.8, 118.7, 118.6, 116.4, 113.8, 113.8, 113.6, 113.6, 113.6, 112.3, 112.1, 104.1, 104.1, 103.9, 103.9, 70.1, 67, 49.6, 45.1, 34.8, 31.5, 31.2, 29.2, 28.5, 23.8.

Example 383: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, m), 3.91 (1H, m), 3.81 (1.8H, m), 3.75-3.65 (2H, m), 3.65-3.59 (1.2H, m), 3.56 (1H, m), 3.35 (3H, 2 s), 3.26 (1H, m), 2.93 (1.8H, s), 2.85 (1H, m), 2.74 (1.2H, s), 2.20 (0.4H, m), 2.10 (0.6H, m), 1.85 (0.4H, m), 1.77 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.2, 156.2, 154.9, 154.9, 129.7, 129.6, 128.3, 128.1, 118.9, 118.8, 118.6, 116.5, 116.4, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 69.4, 69.4, 69.3, 69.2, 67.1, 67, 56.6, 56.5, 53, 49.5, 34.8, 31.5, 31.5, 29.9, 29.8, 29.7, 29.7, 29.4, 29.4, 29.3, 29.2, 29.1, 27.6.

Example 384: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.68 (1H, m), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, m), 5.08 (0.6H, m), 4.61 (0.4H, m), 4.44 (1H, quin, J=8.5 Hz), 4.16 (1H, m), 3.91 (1H, m), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.66 (0.8H, dd, J=7.3, 5.9 Hz), 3.63-3.52 (3H, m), 3.48 (1.2H, s), 3.21 (1H, m), 2.88 (1.8H, d, J=1.5 Hz), 2.82 (1H, m), 2.72 (1.2H, s), 2.22-2.02 (1H, m), 1.88-1.67 (1H, m).

³C NMR (DMSO_(d6)): 168.2, 167.7, 160.1, 160.1, 158.5, 158.5, 156.5, 155.1, 155.1, 154.9, 154.9, 129.7, 129.6, 129.3, 129.2, 118.9, 118.9, 118.9, 118.8, 118.8, 118.7, 118.6, 118.6, 116.1, 116, 115.9, 115.9, 114.3, 114.2, 114.2, 113.3, 113.2, 113.1, 113.1, 69.3, 69.3, 69.3, 67.1, 67.1, 67, 56.5, 52.9, 48.6, 35.6, 30, 29.8, 29.8, 29.8, 29.7, 29.5, 29.5, 29.3, 29.2, 27.6.

Example 385: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=9.0, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.5 Hz), 3.43 (2H, s), 3.40 (3H, s), 3.29 (1H, dd, J=15.9, 9.5 Hz), 2.89 (1H, dd, J=15.8, 8.1 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.7, 118.6, 116.4, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 72.3, 66.3, 49.8, 49.5, 34.7, 32, 31.5, 31.1, 29.2.

Example 386: N-((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 11.76 (1H, s), 7.97 (1H, br d, J=7.5 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.3 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.65 (3H, m), 3.34 (1H, m), 3.25 (2H, s), 3.25 (1H, dd, J=9.5, 15.6 Hz), 3.09 (1H, m), 2.88 (1H, br dd, J=15.7, 8.1 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.45 (2H, m).

¹³C NMR (DMSO_(d6)): 167.2, 155.1, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.8, 120.5, 120.4, 120.3, 114.4, 105.9, 105.7, 105.5, 70.2, 67, 48.4, 45.1, 35.7, 31.4, 29.2, 28.6, 23.9.

Example 387: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 8.18 (1H, t, J=5.7 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.6, 9.2 Hz), 3.83 (2H, m), 3.73 (1H, m), 3.59 (1H, m), 3.46 (2H, m), 3.40 (3H, s), 3.31 (1H, dd, J=9.5, 16.0 Hz), 3.16 (1H, m), 3.10 (1H, m), 2.93 (1H, dd, J=15.9, 8.0 Hz), 1.92-1.72 (3H, m), 1.46 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 156.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.2, 120.4, 120.3, 120.2, 116.5, 105.9, 105.7, 105.6, 77, 67.1, 49.4, 42.9, 34.9, 31.4, 31.2, 29, 28.4, 25.1.

Example 388: N-(1-methyl-2-oxopyrrolidin-3-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 22 from (R)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.40 (1H, dd, J=14.0, 8.1 Hz), 7.48 (1H, qd, J=9.3, 5.0 Hz), 7.19 (1H, m), 4.42 (1H, m), 4.33 (1H, m), 4.23 (1H, m), 3.82 (1H, dd, J=11.4, 8.2 Hz), 3.53-3.43 (2H, m), 3.42 (3H, m), 3.37-3.28 (1H, m), 3.26 (2H, m), 2.93 (1H, m), 2.73 (3H, 2 s), 2.27 (1H, m), 1.76 (1H, m).

¹³C NMR (DMSO_(d6)): 171.3, 167.7, 157, 156.9, 156.3, 155.4, 155.3, 149.1, 149.1, 149, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 128.7, 128.6, 118.8, 118.7, 118.7, 118.6, 118.6, 118.5, 116.5, 116.5, 116.5, 116.5, 116.4, 116.4, 116.3, 116.3, 116.2, 116.1, 112, 112,112, 111.9, 111.8, 111.8, 111.8, 111.8, 111.8, 50.2, 50.1, 49.4, 45.3, 34.8, 31.4, 31.3, 31.3, 29.7, 29.1, 25.7, 25.7.

Example 389: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (R)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.54 (1H, br d, J=6.6 Hz), 7.48 (1H, qd, J=9.4, 5.0 Hz), 7.19 (1H, m), 4.43 (1H, quin, J=8.6 Hz), 4.28 (1H, m), 4.23 (1H, m), 3.81 (1H, dd, J=11.4, 8.0 Hz), 3.61 (1H, dd, J=10.3, 7.0 Hz), 3.44 (2H, d, J=3.2 Hz), 3.40 (3H, s), 3.30 (1H, br dd, J=15.8, 9.4 Hz), 3.11 (1H, dd, J=10.2, 3.6 Hz), 2.90 (1H, br dd, J=15.8, 8.3 Hz), 2.70 (3H, s), 2.57 (1H, dd, J=16.8, 8.6 Hz), 2.11 (1H, dd, J=16.9, 4.1 Hz).

¹³C NMR (DMSO_(d6)): 171.6, 167.7, 157, 156.9, 156.3, 155.3, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.4, 145.9, 145.8, 128.5, 118.9, 118.8, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116.2, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 55.1, 49.5, 42.4, 36.8, 34.7, 31.5, 31.1, 29.1, 28.9.

Example 390: (R)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.48 (1H, qd, J=9.4, 5.0 Hz), 7.19 (1H, m), 4.44 (1H, m), 4.25 (1H, m), 3.91-3.38 (8H, m), 3.38 (3H, s), 3.29 (1H, m), 2.90 (1H, m), 2.32 (0.5H, m), 2.23 (1H, m), 2.10 (0.5H, m).

¹³C NMR (DMSO_(d6)): 166.6, 166.4, 157, 156.9, 156.9, 156.3, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.4, 128.3, 121.1, 120.9, 118.9, 118.9, 118.8, 118.8, 118.8, 118.8, 118.7, 118.7, 116.5, 116.4, 116.4, 116.3, 115.9, 115.9, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 48.7, 48.6, 44.8, 44.6, 34.7, 31.5, 30.2, 30.1, 29.6, 29.1, 28.1, 28, 26.5.

Example 391: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((R)-tetrahydrofuran-2-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(2,3,5,6-terafluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.18 (1H, t, J=5.7 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.6, 9.2 Hz), 3.83 (2H, m), 3.73 (1H, m), 3.59 (1H, m), 3.46 (2H, m), 3.40 (3H, s), 3.31 (1H, dd, J=9.5, 16.0 Hz), 3.16 (1H, m), 3.10 (1H, m), 2.93 (1H, dd, J=15.9, 8.0 Hz), 1.92-1.72 (3H, m), 1.46 (1H, m).

¹³C NMR (DMSO_(d6)): 167.8, 156.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.4, 120.3, 120.2, 116.5, 105.9, 105.7, 105.6, 77, 67.1, 49.4, 42.9, 34.9, 31.5, 31.2, 29, 28.4, 25.1.

Example 392: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a khaki solid.

¹H NMR (DMSO_(d6)): 11.69 (1H, s), 8.26 (1H, br d, J=6.6 Hz), 7.63 (1H, td, J=8.6, 5.6 Hz), 7.21 (1H, t, J=9.2 Hz), 4.24 (1H, m), 4.03 (1H, d, J=12.2 Hz), 3.78 (1H, q, J=7.4 Hz), 3.73 (2H, m), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.48 (1H, dd, J=8.9, 3.7 Hz), 3.31 (2H, m), 2.72 (1H, dd, J=8.3, 4.5 Hz), 2.08 (1H, dq, J=12.7, 7.6 Hz), 1.74 (1H, m), 1.66 (1H, dd, J=8.1, 5.5 Hz), 1.24 (1H, t, J=4.9 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156.1, 155.8, 131.3, 130.3, 130.2, 117.2, 117.1, 117.1, 116.9, 115.7, 115.7, 115.6, 115.6, 114.3, 112.9, 112.9, 112.8, 112.8, 72.4, 66.3, 51.4, 49.8, 32, 31.3, 26.3, 21.6, 21.6, 21.3.

Example 393: (R)-N-(oxetan-3-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.77 (1H, s), 8.72 (1H, br d, J=6.5 Hz), 7.85 (1H, m), 4.76 (1H, m), 4.69 (2H, t, J=6.8 Hz), 4.48 (1H, quin, J=8.5 Hz), 4.41 (2H, t, J=6.0 Hz), 4.17 (1H, dd, J=11.2, 9.5 Hz), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.28 (2H, s), 3.25 (1H, br dd, J=15.9, 9.5 Hz), 2.88 (1H, br dd, J=15.8, 8.0 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 155.3, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129.2, 120.4, 120.3, 120.2, 114, 105.9, 105.7, 105.6, 77, 48.4, 44.1, 35.7, 31.2, 29.2.

Example 394: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a white powder.

¹H NMR (DMSO_(d6)): 8.85 (1H, br d, J=6.6 Hz), 7.86 (1H, m), 4.78 (1H, m), 4.70 (2H, m), 4.48 (1H, quin, J=8.5 Hz), 4.41 (2H, t, J=6.3 Hz), 4.26 (1H, dd, J=11.5, 9.3 Hz), 3.86 (1H, dd, J=11.7, 7.7 Hz), 3.48 (2H, m), 3.39 (3H, m), 3.33 (1H, dd, J=9.5, 16 Hz), 2.94 (1H, dd, J=15.8, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 156.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.4, 120.4, 120.3, 120.2, 116.1, 105.9, 105.7, 105.6, 77, 49.4, 44.2, 34.9, 31.5, 31, 29.

Example 395: 2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(((S)-tetrahydrofuran-2-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a beige powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.03 (1H, br t, J=5.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.2, 9.5 Hz), 3.81 (1H, m), 3.77 (1H, dd, J=11.5, 7.8 Hz), 3.72 (1H, m), 3.58 (1H, m), 3.26 (2H, s), 3.24 (1H, m), 3.16 (1H, m), 3.09 (1H, m), 2.88 (1H, br dd, J=15.8, 8.1 Hz), 1.94-1.68 (3H, m), 1.46 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 155.2, 146.4, 146.4, 146.3, 146.3, 146.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 77, 67.1, 48.4, 42.9, 35.7, 31.4, 29.2, 28.5, 25.1.

Example 396: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 221 step 2 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.62 (1H, br s), 7.63 (1H, td, J=8.6, 5.9 Hz), 7.20 (1H, br t, J=8.9 Hz), 5.11 (0.6H, br s), 4.67 (0.4H, m), 4.04 (1H, br d, J=11.9 Hz), 3.92 (1H, m), 3.80-3.48 (6H, m), 2.90 (1.8H, br s), 2.71 (1.2H, m), 2.67 (1H, m), 2.25-2.01 (1H, m), 1.92-1.72 (1H, m), 1.67 (1H, m), 1.24 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 161.2, 161.2, 159.6, 159.5, 157.8, 157.8, 156.1, 156.1, 156, 155.9, 155.9, 131.4, 130.3, 130.2, 117.1, 115.7, 115.7, 115.6, 115.6, 114.3, 114.2, 112.9, 112.9, 112.8, 112.8, 69.3, 69.3, 69.3, 67.1, 67.1, 67.1, 67, 56.5, 52.9, 51.4, 29.9, 29.8, 29.7, 29.2, 29.2, 27.6, 26.4, 21.8, 21.7, 21.7, 21.7, 21.2, 21.1.

Example 397: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a light cream powder.

¹H NMR (DMSO_(d6)): 8.10 (1H, br t, J=5.7 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.5, 9.3 Hz), 3.82 (3H, m), 3.44 (2H, m), 3.40 (3H, s), 3.31 (1H, m), 3.22 (2H, m), 2.95 (3H, m), 1.62 (1H, m), 1.51 (2H, br d, J=12.5 Hz), 1.12 (2H, m).

¹³C NMR (DMSO_(d6)): 167.8, 156.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 120.4, 120.3, 120.2, 116.6, 105.9, 105.7, 105.6, 66.7, 49.4, 44.5, 34.9, 34.7, 31.5, 31.2, 30.4, 29.1.

Example 398: (R)-N-methyl-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.86 (1H, m), 5.24 (1H, m), 4.72 (1.4H, m), 4.65 (1.3H, br t, J=7.1 Hz), 4.59 (1.3H, m), 4.48 (1H, quin, J=8.3 Hz), 4.24 (1H, m), 3.84 (1H, m), 3.76, 3.73 (2H, 2 s), 3.33 (3H, s), 3.33 (1H, m), 3.11 (1.8H, s), 3.04 (1.2H, s), 2.88 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 156.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 128, 120.5, 120.4, 120.3, 116.3, 116.2, 105.9, 105.7, 105.6, 74.6, 74.6, 74.2, 74.2, 51, 49.4, 49.2, 34.9, 31.5, 31.5, 30.7, 29.6, 29.3, 29, 29, 27.9.

Example 399: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(2-methyl-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, m), 3.92 (1H, m), 3.82 (2H, m), 3.70 (2H, m), 3.63 (1H, m), 3.56 (1H, m), 3.35 (3H, 2 s), 3.26 (1H, m), 2.94 (1.8H, s), 2.86 (1H, m), 2.74 (1.2H, s), 2.21 (0.4H, m), 2.09 (0.6H, m), 1.86 (0.4H, m), 1.76 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 156.2, 154.9, 154.9, 129.7, 129.6, 128.3, 128.1, 118.9, 118.8, 118.7, 116.5, 116.4, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 69.4, 69.2, 67.1, 67.1, 56.6, 53, 49.5, 34.8, 34.8, 31.5, 31.5, 30, 29.8, 29.7, 29.4, 29.3, 29.2, 27.6.

Example 400: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.90 (1H, d, J=6.7 Hz), 7.64 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, m), 4.81 (1H, m), 4.72 (2H, m), 4.44 (2H, td, J=6.4, 1.5 Hz), 4.10 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=12.2 Hz), 3.56 (2H, m), 3.35 (3H, s), 2.79 (1H, dd, J=8.4, 4.4 Hz), 1.69 (1H, dd, J=8.3, 5.5 Hz), 1.27 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.9, 156.2, 156.1, 130.8, 130.3, 130.2, 117, 116.9, 116.8, 116.1, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 77, 77, 52.2, 44.2, 31.5, 31, 25.6, 21.6, 21.2.

Example 401: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.96 (1H, br d, J=7.5 Hz), 7.61 (1H, m), 7.21 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.65 (3H, m), 3.31 (1H, m), 3.26 (2H, s), 3.23 (1H, dd, J=9.4, 15.9 Hz), 3.08 (1H, m), 2.84 (1H, dd, J=15.8, 8.1 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.45 (2H, m).

¹³C NMR (DMSO_(d6)): 167.2, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 129, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.3, 113.2, 113.2, 113.1, 113.1, 70.2, 67, 48.5, 35.6, 31.4, 29.3, 28.6, 23.9.

Example 402: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.74 (1H, s), 7.96 (1H, br d, J=7.6 Hz), 7.71 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.5, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.65 (3H, m), 3.34 (1H, m), 3.25 (2H, d, J=2.9 Hz), 3.21 (1H, dd, J=16.0, 9.1 Hz), 3.09 (1H, dd, J=10.5, 7.8 Hz), 2.83 (1H, dd, J=15.7, 8.2 Hz), 1.79 (1H, m), 1.65 (1H, m), 1.45 (2H, m).

¹³C NMR (DMSO_(d6)): 167.2, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129, 118.8, 118.7, 118.6, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 70.2, 67, 48.6, 45.1, 35.6, 31.4, 29.4, 28.6, 23.9.

Example 403: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.64 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, m), 5.29 (1H, m), 4.76, 4.67, 4.60 (4H, 3 m), 4.11 (1H, m), 3.84 (3H, m), 3.29 (3H, 2 s), 3.16 (1.8H, m), 3.06 (1.2H, s), 2.76 (0.6H, dd, J=8.3, 4.3 Hz), 2.69 (0.4H, dd, J=8.4, 4.4 Hz), 1.68 (1H, m), 1.25 (0.6H, t, J=5.0 Hz), 1.22 (0.4H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.9, 156.2, 156.1, 130.6, 130.3, 130.3, 130.2, 117, 117, 116.9, 116.8, 116.8, 116.3, 116.2, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 74.7, 74.6, 74.3, 74.2, 52.2, 52.2, 51.1, 49.1, 31.5, 31.5, 31.4, 30.7, 29.8, 29.4, 27.9, 25.7, 21.7, 21.2, 21.1.

Example 404: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 8.22 (1H, br d, J=6.6 Hz), 7.61 (1H, td, J=8.8, 5.6 Hz), 7.21 (1H, t, J=9.4 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.21 (1H, tt, J=10.1, 3.8 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.73 (3H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.22 (1H, dd, J=6.3, 11.7 Hz), 2.84 (1H, dd, J=15.6, 8.1 Hz), 2.07 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.5, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 129.1, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.2, 113.3, 113.2, 113.1, 113.1, 72.4, 66.3, 49.8, 48.5, 35.6, 32, 31.3, 29.3.

Example 405: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, td, J=8.4, 5.8 Hz), 7.16 (1H, br t, J=9.4 Hz), 4.38-4.52 (1.6H, m), 4.22 (1H, m), 3.94 (0.4H, m), 3.90 (2H, m), 3.76-3.85 (1.8H, m), 3.72 (1.2H, s), 3.37 (2H, m), 3.35 (3H, s), 3.28 (1H, m), 2.89 (1.8H, s), 2.82-2.88 (1H, m), 2.72 (1.2H, s), 1.74-1.82 (0.8H, m), 1.64-1.74 (1.2H, m), 1.54-1.63 (0.8H, m), 1.37-1.46 (1.2H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.5, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 156.1, 155.9, 155.8, 132.5, 132.4, 128.2, 118.9, 118.8, 118.8, 118.7, 116.7, 116.5, 116.3, 113.8, 113.6, 104.1, 103.9, 66.5, 66.3, 52.9, 49.7, 49.6, 34.8, 31.5, 31.5, 30.2, 30.2, 29.9, 29.5, 29.2, 29.1, 27.1.

Example 406: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.11 (1H, d, J=7.6 Hz), 7.68-7.79 (1H, m), 7.12-7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.71-3.83 (4H, m), 3.42 (2H, d, J=2.3 Hz), 3.40 (3H, s), 3.33 (2H, m), 3.28 (1H, dd, J=15.9, 9.6 Hz), 2.88 (1H, dd, J=15.9, 8.0 Hz), 1.64-1.73 (2H, m), 1.30-1.46 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.7, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.4, 118.8, 118.7, 118.6, 116.4, 113.8, 113.6, 104.1, 104.1, 103.9, 103.9, 65.8, 49.6, 45.2, 34.8, 32.4, 31.5, 31.3, 29.2.

Example 407: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 3 from tert-butyl (4S)-4-(3-chloro-2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 12.56 (1H, br s), 11.78 (1H, s), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, t, J=8.9 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.4, 9.2 Hz), 3.74 (1H, dd, J=11.6, 7.9 Hz), 3.41 (2H, s), 3.26 (1H, dd, J=9.3, 15.8 Hz), 2.87 (1H, dd, J=15.8, 8.2 Hz).

¹³C NMR (DMSO_(d6)): 170.7, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.7, 129.6, 118.8, 118.7, 118.6, 116.1, 116.1, 116, 115.9, 113.4, 113.3, 113.2, 113.1, 113.1, 48.6, 35.6, 29.9, 29.2.

Example 408: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.67 (1H, br s), 7.72 (1H, td, J=8.4, 5.9 Hz), 7.18 (1H, m), 5.22 (1H, m), 4.70 (1.33H, m), 4.63 (1.3H, m), 4.58 (1.3H, m), 4.44 (1Hm), 4.15 (1H, m), 3.69 (1H, m), 3.51, 3.48 (2H, m), 3.18 (1H, m), 3.06, 3.02 (3H, 2 s), 2.80 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 160.8, 160.8, 159.2, 157.5, 157.5, 155.9, 155.8, 155.2, 155.1, 132.5, 132.4, 129.4, 129.3, 118.9, 118.7, 118.6, 114, 113.9, 113.8, 113.6, 104.1, 103.9, 74.6, 74.6, 74.2, 51, 49.1, 48.6, 35.7, 30.8, 29.7, 29.4, 29.3, 29.2, 28.

Example 409: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (4S)-2-(3-ethoxy-3-oxopropanoyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 12.73 (1H, br s), 12.74 (1H, m), 7.53 (1H, m), 7.47 (1H, m), 7.18 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.24 (1H, dd, J=11.4, 9.2 Hz), 3.82 (1H, dd, J=11.6, 7.8 Hz), 3.65 (2H, d, J=0.7 Hz), 3.40 (3H, s), 3.34 (1H, m), 2.92 (1H, dd, J=15.9, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 156.9, 156.9, 156.4, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.7, 118.9, 118.8, 118.8, 118.7, 116.5, 116.5, 116.4, 116.3, 115.6, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 34.7, 31.4, 29.8, 29.1.

Example 410: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.75 (1H, s), 7.97 (1H, d, J=7.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.80 (2H, dt, J=11.4, 3.6 Hz), 3.72 (2H, m), 3.31 (2H, m), 3.24 (2H, s), 3.23 (1H, dd, J=9.4, 16 Hz), 2.83 (1H, dd, J=15.9, 8.1 Hz), 1.67 (2H, m), 1.37 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129, 118.8, 118.7, 118.6, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 65.8, 48.6, 45.2, 35.6, 32.4, 31.5, 29.4.

Example 411: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.47 (1H, qd, J=9.4, 5.1 Hz), 7.18 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.24 (1H, m), 3.81 (1H, dd, J=11.4, 7.9 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.28 (1H, dd, J=15.8, 9.3 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 157, 157, 156.9, 156.9, 156.3, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 66, 66, 49.4, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 412: 2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.5 Hz), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.6 Hz), 4.23 (2H, m), 3.81 (1H, dd, J=11.0, 7.6 Hz), 3.78 (1H, q, J=7.1 Hz), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=9.0, 3.5 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.29 (1H, br dd, J 15.7, 9.2 Hz), 2.90 (1H, dd, J 15.8, 8.2 Hz), 2.08 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 157, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 149, 149, 147.6, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 413: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.84 (1H, br d, J=6.6 Hz), 7.72 (1H, m), 7.18 (1H, m), 4.78 (1H, m), 4.70 (2H, td, J=6.9, 2.2 Hz), 4.42 (3H, m), 4.22 (1H, dd, J=11.4, 9.2 Hz), 3.79 (1H, dd, J=11.6, 7.8 Hz), 3.47 (2H, m), 3.39 (3H, s), 3.28 (1H, dd, J=15.8, 9.3 Hz), 2.89 (1H, dd, J=15.8, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.3, 155.9, 155.9, 132.5, 132.4, 128.7, 118.8, 118.6, 118.5, 116, 113.8, 113.6, 104.1, 104.1, 103.9, 103.9, 77, 77, 49.6, 44.2, 34.8, 31.5, 31, 29.2.

Example 414: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as cream powder.

¹H NMR (DMSO_(d6)): 8.85 (1H, br d, J=6.6 Hz), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.19 (1H, m), 4.78 (1H, m), 4.70 (2H, m), 4.41 (3H, t, J=6.3 Hz), 4.23 (1H, m), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.48 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.91 (1H, dd, J=15.8, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 157, 156.9, 156.3, 155.4, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.8, 128.6, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116.1, 112, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 77, 77, 49.5, 44.2, 34.7, 31.5, 31, 29.1.

Example 415: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.17 (1H, br d, J=7.3 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.21 (1H, m), 4.10 (1H, d, J=12.2 Hz), 3.80 (1H, d, J=12.0 Hz), 3.68 (3H, m), 3.53 (2H, m), 3.39 (1H, m), 3.35 (3H, s), 3.14 (1H, m), 2.78 (1H, dd, J=8.4, 4.4 Hz), 1.83 (1H, m), 1.69 (2H, m), 1.48 (2H, m), 1.25 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.2, 156.1, 130.6, 130.3, 130.2, 117.1, 116.9, 116.8, 116.5, 115.7, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 70.1, 67, 52.2, 45.1, 31.4, 31.1, 28.6, 25.6, 23.9, 21.7, 21.2.

Example 416: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige powder.

¹H NMR (DMSO_(d6)): 8.11 (1H, d, J=7.5 Hz), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=11.4, 9.4 Hz), 3.81 (3H, m), 3.75 (1H, m), 3.42 (2H, m), 3.40 (3H, s), 3.33 (2H, m), 3.29 (1H, dd, J=15.8, 9.2 Hz), 2.90 (1H, dd, J=15.8, 8.3 Hz), 1.69 (2H, m), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 157, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 65.8, 49.4, 45.2, 34.7, 32.4, 31.5, 31.3, 29.2.

Example 417: 2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, d, J=6.6 Hz), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.16 (1H, t, J=9.6 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.23 (2H, m), 3.77 (3H, m), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, br dd, J=9.0, 3.6 Hz), 3.43 (2H, s), 3.40 (3H, m), 3.29 (1H, dd, J=15.8, 9.2 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz), 2.08 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 157, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 418: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a grey solid.

¹H NMR (DMSO_(d6)): 8.41 (1H, d, J=6.7 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.21 (1H, td, J=9.1, 1.2 Hz), 4.25 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.80 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.52 (2H, m), 3.48 (1H, dd, J=8.9, 3.6 Hz), 3.36 (3H, s), 2.79 (1H, dd, J=8.4, 4.4 Hz), 2.09 (1H, dq, J=12.7, 7.6 Hz), 1.74 (1H, m), 1.69 (1H, dd, J=8.4, 5.6 Hz), 1.26 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.2, 156.1, 130.6, 130.3, 130.2, 117.1, 116.9, 116.8, 116.5, 115.7, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 72.4, 66.3, 52.2, 49.8, 32, 31.5, 31, 25.6, 21.7, 21.2.

Example 419: (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.13 (3H, m), 4.23 (1H, dd, J=11.2, 7.8 Hz), 4.07 (1H, quin, J=8.0 Hz), 3.76 (3H, m), 3.60 (2H, br t, J=4.3 Hz), 3.56 (2H, br d, J=4.0 Hz), 3.51 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.20 (1H, dd, J=15.3, 7.9 Hz), 2.84 (1H, dd, J=15.3, 8.4 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 163.3, 163.2, 161.7, 161.6, 156.4, 145.8, 145.7, 145.7, 128.4, 116.6, 110.7, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 66, 51, 45.6, 45.5, 41.7, 31.5, 30.4, 28.7.

Example 420: (R)-N-methyl-N-(oxetan-3-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(2,3,6-trifluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.68 (1H, br s), 7.47 (1H, m), 7.17 (1H, m), 5.22 (1H, m), 4.70 (1.33H, m), 4.63 (1.33H, m), 4.58 (1.33H, m), 4.43 (1H, m), 4.16 (1H, m), 3.74 (1H, m), 3.52, 3.49 (2H, 2s), 3.19 (1H, m), 3.05, 3.01 (3H, 2 s), 2.82 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 157, 155.3, 155.3, 155.2, 155.2, 149.1, 147.5, 147.5, 129.3, 129.2, 118.8, 116.5, 116.4, 116.4, 116.3, 114.1, 114, 112, 111.8, 74.6, 74.6, 74.2, 51, 49.1, 48.5, 35.6, 30.8, 29.7, 29.4, 29.2, 29.1, 28.

Example 421: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 7.64 (1H, td, J=8.7, 5.7 Hz), 7.21 (1H, m), 4.11 (1H, d, J=12.2 Hz), 3.83 (2H, m), 3.80 (1H, d, J=12.2 Hz), 3.62 (2H, m), 3.57 (2H, m), 3.52 (2H, m), 3.47 (2H, m), 3.33 (3H, s), 2.75 (1H, dd, J=8.4, 4.4 Hz), 1.71 (1H, dd, J=8.3, 5.5 Hz), 1.26 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 161.2, 161.2, 159.6, 159.6, 157.8, 157.8, 156.9, 156.1, 156.1, 130.4, 130.3, 130.2, 117, 116.9, 116.8, 116.2, 115.7, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.7, 66, 52.2, 45.7, 41.7, 31.5, 29, 25.7, 21.8, 21.2.

Example 422: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.45 (2H, m), 7.30 (1H, dd, J=10.0, 8.8 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12 Hz), 3.82 (2H, m), 3.62 (2H, m), 3.58 (2H, br t, J=4.8 Hz), 3.53 (2H, m), 3.47 (2H, m), 3.33 (3H, s), 2.86 (1H, dd, J=8.3, 4.2 Hz), 1.72 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 161.3, 159.6, 156.9, 130.7, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.2, 117.6, 117.4, 115.9, 66, 52.4, 52.4, 45.7, 41.7, 31.6, 31.5, 28.9, 22.1, 20.7.

Example 423: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light grey solid.

¹H NMR (DMSO_(d6)): 8.16 (1H, d, J=7.6 Hz), 7.64 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.80 (4H, m), 3.50 (2H, m), 3.36 (3H, s), 3.34 (2H, m), 2.79 (1H, dd, J=8.4, 4.4 Hz), 1.71 (3H, m), 1.41 (2H, m), 1.26 (1H, t, J=5.0 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.2, 156.1, 130.6, 130.3, 130.2, 117.1, 116.9, 116.8, 116.6, 115.7, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 65.8, 52.2, 45.2, 32.4, 32.3, 31.4, 31.3, 25.6, 21.7, 21.3.

Example 424: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (4S)-2-(3-ethoxy-3-oxopropanoyl)-4-(3-chloro-2,6-difluorophenyl)pyrrolidine-1-carboxylate and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 12.73 (1H, s), 7.62 (1H, td, J=8.8, 5.6 Hz), 7.22 (1H, m), 4.46 (1H, m), 4.24 (1H, dd, J=11.6, 9.2 Hz), 3.81 (1H, dd, J=11.6, 7.6 Hz), 3.65 (2H, m), 3.40 (3H, s), 3.33 (1H, dd, J=9.3, 15.9 Hz), 2.91 (1H, dd, J=16.1, 8.1 Hz).

¹³C NMR (DMSO_(d6)): 170.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.4, 154.9, 154.9, 129.7, 129.7, 128.7, 118.8, 118.7, 118.6, 116.1, 116, 116, 115.9, 115.5, 113.3, 113.2, 113.1, 113.1, 49.6, 34.7, 31.4, 29.8, 29.1.

Example 425: 2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.13 (3H, m), 4.23 (2H, m), 4.07 (1H, quin, J=8.0 Hz), 3.76 (3H, m), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.46 (3H, m), 3.40 (3H, s), 3.23 (1H, dd, J=15.4, 7.9 Hz), 2.86 (1H, dd, J=15.4, 8.4 Hz), 2.08 (1H, m), 1.72 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 163.3, 163.2, 161.7, 161.6, 156.4, 145.8, 145.8, 145.7, 128.5, 116.6, 110.7, 110.7, 110.6, 110.5, 102.6, 102.5, 102.3, 72.4, 66.3, 51.1, 49.8, 45.4, 32, 31.5, 31, 30.4.

Example 426: 2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3,5-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.37 (1H, br d, J=6.6 Hz), 7.13 (3H, m), 4.23 (2H, m), 4.07 (1H, quin, J=8.0 Hz), 3.75 (3H, m), 3.67 (1H, td, J=8.3, 5.5 Hz), 3.48 (1H, br d, J=3.5 Hz), 3.45 (2H, s), 3.40 (3H, s), 3.23 (1H, dd, J=15.4, 7.9 Hz), 2.86 (1H, dd, J=15.3, 8.3 Hz), 2.08 (1H, m), 1.72 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 163.3, 163.2, 161.7, 161.6, 156.4, 145.9, 145.8, 145.7, 128.5, 116.6, 110.7, 110.7, 110.6, 110.5, 102.6, 102.5, 102.3, 72.4, 66.3, 51.1, 49.8, 45.4, 32, 31.5, 31, 30.4.

Example 427 (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.10 (1H, br t, J=5.8 Hz), 7.47 (1H, qd, J=9.5, 4.9 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.23 (1H, dd, J=11.3, 9.4 Hz), 3.81 (3H, m), 3.44 (2H, m), 3.40 (3H, s), 3.29 (1H, dd, J=15.9, 9.2 Hz), 3.22 (2H, tt, J=11.7, 2.3 Hz), 2.96 (2H, m), 2.90 (1H, dd, J=15.8, 8.3 Hz), 1.62 (1H, m), 1.51 (2H, m), 1.13 (2H, m).

¹³C NMR (DMSO_(d6)): 167.8, 157, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 149, 149, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 66.7, 49.4, 44.5, 34.7, 34.7, 31.5, 31.2, 30.4, 29.2.

Example 428: (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(3,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.10 (1H, t, J=5.8 Hz), 7.13 (3H, m), 4.23 (1H, dd, J=11.2, 7.9 Hz), 4.07 (1H, quin, J=8.0 Hz), 3.82 (2H, m), 3.75 (1H, dd, J=11.2, 7.8 Hz), 3.46 (2H, m), 3.40 (3H, s), 3.22 (3H, m), 2.97 (2H, m), 2.85 (1H, dd, J=15.4, 8.2 Hz), 1.63 (1H, m), 1.51 (2H, m), 1.14 (2H, m).

¹³C NMR (DMSO_(d6)): 167.8, 163.3, 163.2, 161.7, 161.6, 156.4, 145.9, 145.9, 145.8, 128.6, 116.7, 110.7, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 66.7, 51.2, 45.4, 44.5, 34.8, 31.4, 31.1, 30.4, 30.4.

Example 429: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 5.24 (1H, m), 4.72, 4.64, 4.59 (4H, m), 4.43 (1H, m), 4.23 (1H, m), 3.80 (1H, m), 3.75, 3.72 (2H, m), 3.33 (3H, s), 3.24 (1H, m), 3.11 (1.8H, s), 3.03 (1.2H, s), 2.83 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 128.1, 118.9, 118.8, 118.6, 116.3, 116.1, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 74.6, 74.6, 74.2, 74.2, 51, 49.5, 49.2, 34.8, 31.5, 31.5, 30.7, 29.6, 29.3, 29.1, 29.1, 27.9.

Example 430: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.70 (0.4H, s), 7.62 (1H, td, J=8.7, 5.6 Hz), 7.59 (0.6H, s), 7.41 (0.4H, s), 7.31 (0.6H, s), 7.22 (1H, m), 4.42 (1.8H, m), 4.32 (0.6H, m), 4.27 (0.6H, m), 4.21 (1H, m), 3.80 (3H, m), 3.71 (3H, m), 3.36 (3H, 2 s), 3.21 (1H, m), 2.97 (1.8H, s), 2.81 (1.2H, s), 2.80 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 167.5, 160.1, 160.1, 158.5, 158.5, 156.6, 156.6, 156.5, 156.5, 156.2, 154.9, 154.9, 154.9, 154.9, 138.4, 137.8, 129.9, 129.7, 129.6, 129.5, 128.2, 128.2, 118.8, 118.8, 118.7, 118.6, 118.6, 116.7, 116.6, 116.5, 116.4, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 49.5, 43.6, 41, 38.5, 38.3, 34.7, 34.7, 34.6, 33, 31.5, 31.5, 29.4, 29.1, 29.1, 29.

Example 431: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.45 (2H, m), 7.30 (1H, dd, J=10.1, 8.7 Hz), 5.29 (1H, m), 4.77, 4.74, 4.66, 4.61 (4H, 4 m), 4.15 (1H, m), 3.83 (3H, m), 3.30 (3H, 2 s), 3.16 (1.8H, s), 3.06 (1.2H, s), 2.87 (0.6H, dd, J=8.4, 4.3 Hz), 2.79 (0.4H, dd, J=8.3, 4.2 Hz), 1.69 (1H, m), 1.12 (0.6H, t, J=4.8 Hz), 1.09 (0.4H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 161.3, 159.6, 156.9, 130.9, 130.6, 130.3, 130.2, 130.2, 129.4, 129.3, 128.7, 128.7, 128.6, 128.6, 128.3, 128.3, 117.6, 117.4, 116, 115.8, 74.7, 74.6, 74.3, 74.2, 52.4, 51.1, 49.1, 31.6, 31.5, 31.5, 30.7, 29.7, 29.4, 27.9, 22.1, 22, 20.7, 20.6.

Example 432: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 8.85 (1H, d, J=6.6 Hz), 7.47 (1H, qd, J=9.5, 5.0 Hz), 7.18 (1H, m), 4.79 (1H, m), 4.70 (2H, m), 4.41 (3H, m), 4.23 (1H, dd, J=11.4, 9.2 Hz), 3.81 (1H, dd, J=11.6, 7.9 Hz), 3.48 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.2 Hz), 2.91 (1H, dd, J=15.8, 8.3 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 157, 156.9, 156.3, 155.4, 155.3, 149.1, 149, 149, 149, 147.6, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.6, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 77, 77, 49.5, 44.2, 34.7, 31.5, 31, 29.1.

Example 433: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.87 (1H, d, J=6.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=10.1, 8.8 Hz), 4.82 (1H, m), 4.72 (2H, dd, J=7.4, 6.1 Hz), 4.44 (2H, td, J=6.3, 2.6 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.55 (2H, m), 3.34 (3H, s), 2.90 (1H, dd, J=8.4, 4.0 Hz), 1.69 (1H, dd, J=8.4, 5.3 Hz), 1.15 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.5, 161.3, 159.6, 156.9, 131.2, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 115.7, 77, 77, 52.4, 52.4, 44.2, 31.6, 31.5, 30.9, 22, 20.7.

Example 434: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.44 (2H, m), 7.30 (1H, m), 4.49 (0.6H, m), 4.15 (1H, br d, J=12.0 Hz), 4.01 (0.4H, m), 3.85 (3H, m), 3.80 (1H, m), 3.41 (3H, m), 3.31 (3H, m), 2.93 (2.2H, m), 2.87 (0.6H, dd, J=8.4, 4.3 Hz), 2.74 (1.2H, s), 1.87-1.59 (3.8H, m), 1.43 (1.2H, m), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 161.3, 159.6, 156.9, 156.8, 130.8, 130.7, 130.2, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.4, 116.2, 66.5, 66.3, 53, 52.4, 49.8, 31.7, 31.6, 31.5, 31.5, 30.2, 30, 29.6, 29.3, 29.2, 29.1, 27.1, 22.2, 22.1, 20.7, 20.7.

Example 435: (S)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a yellowish powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.17 (1H, m), 5.24 (1H, m), 4.73, 4.64, 4.59 (4H, m), 4.42 (1H, m), 4.24 (1H, m), 3.81 (1H, m), 3.73 (2H, m), 3.33 (3H, 2 s), 3.25 (1H, m), 3.11 (1.8H, s), 3.03 (1.2H, s), 2.87 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 157, 156.9, 156.9, 156.3, 155.3, 155.3, 149.2, 149.1, 149, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 128.4, 128.1, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.2, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 74.6, 74.6, 74.2, 74.2, 51, 49.4, 49.2, 34.7, 34.7, 31.5, 31.5, 31.4, 30.7, 29.9, 29.6, 29.3, 29.1, 29.1, 27.9.

Example 436: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a khaki solid.

¹H NMR (DMSO_(d6)): 7.57 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.1 Hz), 3.82 (2H, m), 3.64 (2H, m), 3.58 (2H, m), 3.53 (2H, m), 3.47 (2H, m), 3.33 (3H, 2 s), 2.86 (1H, dd, J=8.4, 4.3 Hz), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 166.9, 161.8, 160.2, 156.9, 133.1, 133.1, 132.4, 132.3, 130.7, 129.1, 129, 118, 117.9, 116.2, 116.2, 115.9, 66, 52.4, 45.7, 41.7, 31.6, 31.5, 28.9, 22.1, 20.7.

Example 437: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a grey solid.

¹H NMR (DMSO_(d6)): 8.87 (1H, d, J=6.7 Hz), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.82 (1H, m), 4.72 (2H, t, J=6.8 Hz), 4.44 (2H, td, J=6.4, 2.3 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.55 (2H, m), 3.34 (3H, br s), 2.90 (1H, dd, J=8.4, 4.1 Hz), 1.69 (1H, dd, J=8.4, 5.4 Hz), 1.15 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.6, 161.8, 160.1, 156.9, 133.1, 133, 132.4, 132.3, 131.2, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 115.7, 77, 77, 52.5, 52.4, 44.2, 31.5, 31.5, 30.9, 22, 20.7.

Example 438: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.56 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 5.29 (1H, m), 4.75, 4.66, 4.62 (4H, 4 m), 4.14 (1H, m), 3.83 (3H, m), 3.29 (3H, 2 s), 3.15 (1.8H, s), 3.06 (1.2H, s), 2.87 (0.6H, dd, J=8.3, 4.2 Hz), 2.79 (0.4H, dd, J=8.3, 4.2 Hz), 1.69 (1H, m), 1.12 (0.6H, t, J=4.8 Hz), 1.08 (0.4H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 161.8, 160.2, 156.9, 133.1, 133.1, 133, 132.4, 132.3, 130.9, 130.6, 129.2, 129.1, 129.1, 129, 118, 117.8, 116.2, 116.2, 116, 115.8, 74.7, 74.6, 74.3, 74.2, 52.4, 51.1, 49.1, 31.6, 31.5, 31.5, 30.7, 29.7, 29.3, 27.9, 22.1, 22, 20.6, 20.6.

Example 439: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a a light beige solid.

¹H NMR (DMSO_(d6)): 77.57 (2H, m), 7.24 (1H, m), 4.49 (0.6H, m), 4.15 (1H, br d, J=11.6 Hz), 4.01 (0.4H, m), 3.97-3.73 (5H, m), 3.51-3.24 (5H, m), 2.93 (2.2H, m), 2.87 (0.6H, dd, J=8.3, 4.2 Hz), 2.74 (1.2H, s), 1.88-1.58 (3.8H, m), 1.45 (1.2H, m), 1.12 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 161.8, 160.1, 156.9, 156.8, 133, 132.4, 132.3, 130.7, 130.7, 129.2, 129.1, 118, 117.8, 116.4, 116.2, 116.2, 66.5, 66.3, 52.9, 52.4, 49.7, 31.6, 31.5, 31.5, 31.5, 30.2, 30.2, 30, 29.6, 29.3, 29.2, 29.1, 27.1, 22.2, 22.1, 20.7, 20.6.

Example 440: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a light yellow solid.

¹H NMR (DMSO_(d6)): 7.58 (2H, m), 7.25 (1H, dd, J=10.1, 8.9 Hz), 5.13 (0.6H, m), 4.73 (0.4H, m), 4.16 (1H, d, J=11.9 Hz), 4.0-3.51 (7H, m), 3.32 (3H, 2 s), 2.98 (1.8H, s), 2.87 (1H, m), 2.77 (1.2H, s), 2.26 (0.4H, m), 2.15 (0.6H, m), 1.91 (0.4H, m), 1.81 (0.6H, m), 1.70 (1H, m), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 167.6, 161.8, 161.8, 160.2, 160.1, 156.9, 156.8, 133.1, 133, 132.4, 132.3, 130.8, 130.7, 130.6, 129.2, 129.1, 129.1, 129, 118, 117.8, 116.2, 116.2, 116.1, 69.4, 69.3, 67.1, 67.1, 67, 53, 52.4, 31.6, 31.6, 31.5, 31.5, 31.3, 29.9, 29.9, 29.8, 29.4, 29.3, 27.7, 22.1, 21.6, 20.7.

Example 441: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.45 (2H, m), 7.30 (1H, m), 5.13 (0.6H, m), 4.73 (0.4H, m), 4.15 (1H, br d, J=11.9 Hz), 4.0-3.52 (7H, m), 3.31 (3H, 2 s), 2.97 (1.8H, s), 2.86 (1H, m), 2.76 (1.2H, s), 2.26 (0.4H, m), 2.13 (0.6H, m), 1.91 (0.4H, m), 1.80 (0.6H, m), 1.69 (1H, m), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 161.3, 161.3, 159.7, 159.6, 156.9, 156.8, 130.8, 130.7, 130.6, 130.2, 129.4, 129.3, 128.8, 128.7, 128.7, 128.6, 128.3, 117.6, 117.4, 116.2, 116.1, 69.4, 69.4, 69.3, 67.1, 67.1, 56.6, 53, 52.4, 31.6, 31.5, 31.5, 29.9, 29.9, 29.8, 29.8, 29.4, 29.3, 27.7, 22.1, 20.7, 20.7.

Example 442: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 7.63 (1H, m), 7.21 (1H, br t, J=9.0 Hz), 5.11 (0.6H, m), 4.72 (0.4H, m), 4.11 (1H, br d, J=12.2 Hz), 4.0-3.51 (7H, m), 3.32 (3H, 2 s), 2.96 (1.8H, s), 2.76 (2.2H, m), 2.25 (0.4H, m), 2.12 (0.6H, m), 1.89 (0.4H, m), 1.79 (0.6H, m), 1.68 (1H, m), 1.27 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.9, 156.8, 156.2, 156.1, 130.4, 130.3, 130.2, 117, 117, 116.9, 116.8, 116.8, 116.6, 116.4, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 69.3, 69.3, 67.1, 67.1, 67.1, 64.9, 56.6, 53, 52.2, 31.5, 31.5, 29.9, 29.9, 29.9, 29.8, 29.5, 29.5, 29.3, 29.2, 27.7, 27.6, 25.7, 21.8, 21.7, 21.2, 21.1.

Example 443: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 7.64 (1H, m), 7.21 (1H, br t, J=9.1 Hz), 4.49 (0.6H, m), 4.11 (1H, dd, J=12.2, 2.2 Hz), 4.02 (0.4H, m), 3.98-3.74 (4.8H, m), 3.38 (2.2H, m), 3.32 (3H, 2 s), 2.92 (1.8H, s), 2.81 (0.4H, br dd, J=8.3, 4.3 Hz), 2.76 (0.6H, br d, J=4.3, 8.3 Hz), 2.74 (1.2H, s), 1.87-1.58 (4H, m), 1.44 (1H, m), 1.25 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.8, 156.2, 156.1, 130.4, 130.3, 130.3, 130.2, 117.1, 116.9, 116.8, 116.7, 116.5, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 66.5, 66.5, 66.3, 53, 52.2, 31.5, 31.5, 30.2, 30.2, 30.1, 29.6, 29.3, 29.2, 29.1, 27.1, 25.7, 25.7, 21.9, 21.7, 21.2, 21.2, 21.2.

Example 444: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(isoxazolidin-2-yl)ethan-1-one

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.62 (1H, td, J=8.8, 5.6 Hz), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=11.5, 9.2 Hz), 3.97 (2H, t, J=6.8 Hz), 3.81 (1H, dd, J=11.6, 7.8 Hz), 3.75 (2H, br s), 3.59 (2H, m br), 3.39 (3H, s), 3.30 (1H, dd, J=9.3, 15.9 Hz), 2.90 (1H, dd, J=15.8, 8.1 Hz), 2.26 (2H, quin, J=7.1 Hz).

¹³C NMR (DMSO_(d6)): 168.5, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 129.7, 129.7, 128.8, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 115.5, 113.3, 113.2, 113.1, 113.1, 69.3, 49.5, 43.3, 34.7, 31.5, 29.1, 28.5, 27.2.

Example 445: (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.41 (1H, m), 7.14 (2H, t, J=8.1 Hz), 4.41 (1H, quin, J=8.7 Hz), 4.22 (1H, m), 3.78 (1H, dd, J=11.4, 8.1 Hz), 3.75 (2H, s), 3.60 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.44 (2H, m), 3.36 (3H, m), 3.25 (1H, dd, J=9.3, 15.9 Hz), 2.86 (1H, dd, J=15.7, 8.5 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 161.6, 161.5, 160, 159.9, 156.3, 129.8, 129.7, 129.7, 128.3, 116.6, 116.5, 116.4, 116.2, 112.3, 112.2, 112.1, 112.1, 66, 66, 49.6, 45.6, 41.7, 34.4, 31.5, 29.3, 28.8.

Example 446: 2-((R)-6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.36 (1H, br d, J=6.6 Hz), 7.41 (1H, tt, J=8.4, 6.5 Hz), 7.14 (2H, m), 4.41 (1H, quin, J=8.8 Hz), 4.22 (2H, m), 3.77 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.3, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.7 Hz), 3.43 (2H, s), 3.40 (3H, s), 3.26 (1H, dd, J=15.7, 9.2 Hz), 2.88 (1H, dd, J=15.7, 8.5 Hz), 2.08 (1H, m), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 161.6, 161.5, 160, 159.9, 156.2, 129.8, 129.8, 129.7, 128.5, 116.6, 116.4, 116.4, 116.3, 112.3, 112.2, 112.1, 112.1, 72.4, 66.3, 49.8, 49.6, 34.4, 32, 31.5, 31.1, 29.3.

Example 447 (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.11 (1H, br d, J=7.5 Hz), 7.41 (1H, m), 7.14 (2H, m), 4.41 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=10.8, 9.8 Hz), 3.77 (4H, m), 3.42 (2H, m), 3.40 (3H, s), 3.33 (1H, m), 3.26 (1H, dd, J=15.7, 9.2 Hz), 2.88 (1H, dd, J=15.7, 8.5 Hz), 1.69 (2H, m), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 166.9, 161.6, 161.5, 160, 159.9, 156.2, 129.8, 129.8, 129.7, 128.5, 116.6, 116.5, 116.3, 112.3, 112.2, 112.1, 112.1, 65.8, 49.6, 45.2, 34.4, 32.4, 31.5, 31.3, 29.3.

Example 448: (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.41 (1H, m), 7.13 (2H, m), 5.24 (1H, m), 4.72, 4.64, 4.59 (4H, m), 4.40 (1H, m), 4.22 (1H, m), 3.79 (1H, m), 3.75 (2H, 2 s), 3.34 (3H, s), 3.22 (1H, m), 3.11 (1.8H, s), 3.03 (1.2H, s), 2.83 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 161.6, 161.5, 160, 159.9, 156.2, 129.8, 129.7, 129.7, 128.5, 128.3, 116.6, 116.5, 116.4, 116.3, 116.1, 112.3, 112.2, 112.1, 112.1, 74.6, 74.6, 74.2, 74.2, 51, 49.6, 49.2, 34.4, 31.5, 31.5, 30.7, 29.6, 29.3, 29.2, 29.2, 27.9.

Example 449: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.54 (1H, br d, J=6.6 Hz), 7.73 (1H, td, J=8.4, 5.7 Hz), 7.18 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.28 (1H, m), 4.22 (1H, dd, J=11.4, 9.2 Hz), 3.79 (1H, dd, J=11.6, 7.8 Hz), 3.60 (1H, dd, J=10.2, 7.0 Hz), 3.43 (2H, d, J=2.6 Hz), 3.39 (3H, s), 3.28 (1H, dd, J=9.6, 15.9 Hz), 3.11 (1H, dd, J=10.3, 3.5 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz), 2.70 (3H, s), 2.58 (1H, ddd, J=16.9, 8.5, 0.7 Hz), 2.11 (1H, dd, J=16.9, 4.3 Hz).

¹³C NMR (DMSO_(d6)): 171.7, 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.5, 118.8, 118.7, 118.5, 116.1, 113.8, 113.6, 104.1, 104.1, 103.9, 55.1, 49.6, 42.5, 36.8, 34.8, 31.5, 31.1, 29.2, 28.9.

Example 450: (S)-1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile

Compound was prepared analogous manner to Example 25 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, t, J=9.4 Hz), 4.44 (1H, m), 4.23 (1H, dd, J=11.4, 9.2 Hz), 3.89-3.73 (2H, m), 3.73-3.58 (3.5H, m), 3.55 (1H, m), 3.49-3.37 (1.5H, m), 3.37 (3H, s), 3.29 (1H, m), 2.87 (1H, m), 2.31 (0.5H, m), 2.22 (1H, m), 2.09 (0.5H, m).

¹³C NMR (DMSO_(d6)): 166.6, 166.4, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.5, 128.4, 121.1, 120.9, 118.9, 118.8, 118.8, 118.7, 118.6, 118.6, 115.9, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 49.6, 48.7, 48.6, 44.8, 44.6, 34.8, 34.8, 31.5, 30.2, 30.1, 29.6, 29.2, 28.1, 28, 26.5.

Example 451: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(2-methyl-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, s), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.43 (1H, m), 4.22 (1H, dd, J=11.3, 9.4 Hz), 3.92 (1H, m), 3.81 (1.8H, m), 3.69 (2.2H, m), 3.63 (1H, m), 3.56 (1H, m), 3.36 (3H, m), 3.25 (1H, m), 2.93 (1.8H, s), 2.85 (1H, m), 2.74 (1.2H, s), 2.21 (0.4H, m), 2.09 (0.6H, m), 1.86 (0.4H, m), 1.76 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 156.2, 156.1, 155.9, 155.9, 132.5, 132.4, 128.3, 128.1, 118.9, 118.8, 118.6, 116.5, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 69.4, 69.2, 67.1, 67, 56.6, 53, 49.5, 34.8, 34.8, 31.5, 31.5, 29.9, 29.8, 29.7, 29.4, 29.3, 29.2, 29.2, 27.6.

Example 452: (S)-1-(2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpiperidine-4-carboxamide

Compound was prepared analogous manner to Example 25 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one using DIPEA as base and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, td, J=8.3, 5.9 Hz), 7.16 (1H, t, J=9.1 Hz), 4.44 (1H, quin, J=8.5 Hz), 4.35 (1H, m), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.91 (1H, br d, J=12.6 Hz), 3.80 (1H, m), 3.75 (2H, s), 3.36 (3H, m), 3.26 (1H, m), 3.11 (1H, m), 3.03 (3H, s), 2.87 (2H, m), 2.80 (3H, s), 2.67 (1H, m), 1.65 (2H, m), 1.53 (1H, m), 1.33 (1H, m).

¹³C NMR (DMSO_(d6)): 173.5, 166.2, 166.2, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.2, 118.8, 118.7, 118.6, 116.6, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.5, 44.7, 40.8, 40.8, 37.1, 36.6, 35, 34.8, 31.5, 29.2, 29, 28.9, 28.6, 27.9.

Example 453: 1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpyrrolidine-3-carboxamide

Compound was prepared analogous manner to Example 25 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, t, J=9.4 Hz), 4.44 (1H, m), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.79 (1H, br dd, J=11.4, 7.8 Hz), 3.75-3.41 (5.5H, m), 3.38 (3H, s), 3.41-3.21 (2.5H, m), 3.03-3.01 (3H, 3 s), 2.88 (1H, m), 2.83-2.79 (3H, 4 s), 2.12 (0.5H, m), 2.04 (0.5H, m), 1.99 (0.5H, m), 1.85 (0.5H, m).

¹³C NMR (DMSO_(d6)): 171.7, 171.3, 171.3, 166.1, 166, 166, 166, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 156.2, 155.9, 155.9, 132.5, 132.4, 128.3, 118.9, 118.8, 118.8, 118.8, 118.8, 118.7, 118.7, 118.6, 118.6, 118.6, 116.2, 116.2, 116.1, 116.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.5, 49.5, 48.7, 48.4, 45.8, 45.3, 45.2, 40.2, 38.3, 38.3, 36.7, 35.1, 35.1, 35, 34.8, 34.8, 31.5, 30.3, 30.3, 30.3, 30.2, 29.2, 29.1, 29, 27.5.

Example 454: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, td, J=8.4, 5.9 Hz), 7.17 (1H, m), 5.24 (1H, m), 4.72 (1.33H, m), 4.64 (1.33H, m), 4.59 (1.33H, m), 4.43 (1H, m), 4.22 (1H, m), 3.75 (3H, m), 3.33 (3H, s), 3.23 (1H, m), 3.11 (1.8H, s), 3.03 (1.2H, s), 2.82 (1H, m).

¹³C NMR (DMSO_(d6)): 168.6, 167.8, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.4, 128.2, 118.9, 118.8, 118.6, 116.2, 116.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 74.6, 74.6, 74.2, 74.2, 51, 49.6, 49.2, 34.8, 31.5, 31.5, 30.7, 29.6, 29.3, 29.2, 29.1, 27.9.

Example 455: N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.47 (1H, m), 7.18 (1H, m), 5.09 (0.6H, m), 4.66 (0.4H, m), 4.43 (1H, m), 4.24 (1H, m), 3.92 (1H, m), 3.82 (1.8H, m), 3.71 (2.2H, m), 3.62 (1H, m), 3.56 (1H, m), 3.33 (3H, 2 s), 3.27 (1H, m), 2.93 (1.8H, s), 2.86 (1H, m), 2.74 (1.2H, s), 2.21 (0.4H, m), 2.10 (0.6H, m), 1.86 (0.4H, m), 1.79 (0.6H, m).

¹³C NMR (DMSO_(d6)): 168.2, 167.6, 157, 156.9, 156.9, 156.2, 156.2, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.4, 147.4, 147.4, 145.9, 145.9, 145.8, 128.2, 128.1, 118.9, 118.8, 118.8, 118.8, 118.7, 116.6, 116.5, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 69.4, 69.3, 67.1, 67.1, 56.5, 53, 49.4, 34.8, 31.5, 31.5, 30, 29.7, 29.7, 29.4, 29.3, 29.1, 29.1, 27.6.

Example 456: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 8 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (analogous to Example 229) and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.17 (1H, m), 4.78 (1H, t, J=5.3 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.20 (1H, dd, J=11.5, 9.3 Hz), 3.78 (1H, dd, J=11.6, 7.9 Hz), 3.58 (2H, td, J=6.5, 5.3 Hz), 3.43 (3H, s), 3.31 (1H, m), 2.94 (1H, dd, J=15.7, 8.2 Hz), 2.65 (2H, t, J=6.4 Hz).

¹³C NMR (DMSO_(d6)): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156, 155.9, 155.8, 132.5, 132.4, 127.5, 119.4, 118.8, 118.6, 118.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 58.9, 49.3, 34.8, 31.3, 29.3, 27.7.

Example 457: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide

Compound was prepared analogous manner to Example 22 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 78.35 (1H, m), 7.74 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.5, 9.2 Hz), 4.04 (1H, m), 3.79 (1H, dd, J=11.7, 7.7 Hz), 3.47 (2H, m), 3.42 (1H, m), 3.41 (3H, s), 3.28 (1H, m), 3.08 (1H, m), 2.88 (1H, dd, J=15.9, 8.0 Hz), 2.77 (3H, 2 s), 2.28 (2H, m), 1.86 (1H, m), 1.75 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 167.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.5, 128.4, 118.8, 118.7, 118.6, 116.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 52.9, 49.6, 43.4, 43.4, 34.8, 33.9, 31.5, 31.1, 31.1, 29.2, 29, 29, 26.1.

Example 458: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(fluoromethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 7.72 (1H, m), 7.16 (1H, t, J=9.4 Hz), 4.44 (3H, m), 4.22 (1H, dd, J=11.4, 9.2 Hz), 3.80 (1H, m), 3.70 (0.5H, m), 3.65 (2H, d, J=5.9 Hz), 3.61 (0.5H, m), 3.48 (1.5H, m), 3.37 (3H, 2 s), 3.28 (2H, m), 3.11 (0.5H, m), 2.85 (1H, m), 2.65 (0.5H, m), 2.56 (0.5H, m), 2.04 (0.5H, m), 1.92 (0.5H, m), 1.75 (0.5H, m), 1.62 (0.5H, m).

¹³C NMR (DMSO_(d6)): 166.3, 166.3, 160.8, 160.7, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.3, 128.3, 128.3, 118.9, 118.8, 118.7, 116.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 84.8, 84.8, 83.7, 83.7, 49.6, 48, 47.9, 47.2, 47.2, 45.4, 45, 37.3, 37.2, 37.1, 37.1, 34.8, 31.5, 31.5, 30.3, 30.1, 30.1, 29.2, 27.2, 27.1, 25.4, 25.4, 25.4, 25.4.

Example 459: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 8.36 (1H, d, J=6.6 Hz), 7.72 (1H, m), 7.16 (1H, t, J=9.3 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.3, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.5 Hz), 3.43 (2H, s), 3.40 (3H, s), 3.28 (1H, dd, J=15.8, 9.5 Hz), 2.88 (1H, dd, J=15.8, 7.9 Hz), 2.08 (1H, dq, J=12.8, 7.6 Hz), 1.71 (1H, m).

¹³C NMR (DMSO_(d6)): 167.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.4, 118.8, 118.7, 118.6, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 72.4, 66.3, 49.8, 49.6, 34.8, 32, 31.5, 31.1, 29.2.

Example 460: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d₃)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 7.61 (1H, td, J=8.8, 5.6 Hz), 7.22 (1H, td, J=9.5, 1.6 Hz), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, dd, J=11.5, 9.2 Hz), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.74 (2H, s), 3.60 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.44 (2H, m), 3.27 (1H, dd, J=15.8, 9.4 Hz), 2.86 (1H, dd, J=15.8, 7.9 Hz).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.2, 118.9, 118.8, 118.6, 116.2, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 66, 66, 49.5, 45.6, 41.7, 34.8, 29.2, 28.8.

Example 461: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.39 (1H, d, J=6.7 Hz), 7.58 (1H, m), 7.56 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.80 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.6, 8.9 Hz), 2.88 (1H, dd, J=8.4, 4.2 Hz), 2.10 (1H, m), 1.74 (1H, m), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 161.8, 160.2, 156.8, 133.1, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 116.1, 72.4, 66.3, 52.4, 49.8, 32, 31.5, 31, 22.1, 20.7.

Example 462: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a beige solid.

¹H NMR (DMSO_(d6)): 12.78 (1H, br s), 7.57 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.16 (1H, d, J=11.9 Hz), 3.86 (1H, d, J=12.0 Hz), 3.75 (2H, m), 2.97 (1H, dd, J=8.5, 4.1 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 170.9, 161.8, 160.2, 157, 133, 133, 132.4, 132.3, 131.2, 129.1, 129, 118, 117.9, 116.2, 116.2, 115.2, 52.5, 52.4, 31.5, 29.7, 22.1, 20.6.

Example 463: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.14 (1H, d, J=7.5 Hz), 7.58 (1H, m), 7.56 (1H, ddd, J=6.5, 4.4, 2.3 Hz), 7.24 (1H, dd, J=10.2, 8.7 Hz), 4.14 (1H, d, J=11.9 Hz), 3.85 (1H, d, J=12.2 Hz), 3.82 (2H, m), 3.77 (1H, m), 3.49 (2H, m), 3.33 (2H, m), 2.88 (1H, dd, J=8.4, 3.9 Hz), 1.71 (3H, m), 1.40 (2H, m), 1.13 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167, 161.8, 160.2, 156.8, 133.1, 133.1, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 116.2, 65.9, 52.4, 45.2, 32.4, 32.4, 31.5, 31.2, 22.1, 20.7.

Example 464: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.14 (1H, br d, J=7.5 Hz), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.71 (2H, m), 3.65 (1H, dt, J=11.1, 4.3 Hz), 3.51 (2H, m), 3.39 (1H, m), 3.14 (1H, m), 2.88 (1H, dd, J=8.5, 4.1 Hz), 1.83 (1H, br d, J=12.0 Hz), 1.68 (2H, m), 1.50 (2H, m), 1.12 (1H, t, J=4.8 Hz).

¹³C NMR (DMSO_(d6)): 167.4, 161.8, 160.2, 156.8, 133.1, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 116.1, 70.1, 67, 52.4, 45.2, 31.5, 31.1, 28.6, 23.9, 22.1, 20.7.

Example 465: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d₃)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.40 (1H, d, J=6.7 Hz), 7.58 (1H, m), 7.56 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.80 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.6, 8.9 Hz), 2.88 (1H, dd, J=8.4, 4.2 Hz), 2.10 (1H, m), 1.74 (1H, m), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 167.7, 161.8, 160.2, 156.8, 133.1, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 116.1, 72.3, 66.3, 52.4, 49.8, 32.1, 31.5, 31, 22.1, 20.7.

Example 466: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.58 (2H, m), 7.24 (1H, m), 5.11 (0.6H, m), 4.72 (0.4H, m), 4.15 (1H, d, J=12.1 Hz), 4.0-3.51 (7H, m), 3.31 (3H, 2 s), 2.98 (1.8H, s), 2.86 (1H, m), 2.76 (1.2H, s), 2.24 (0.4H, m), 2.12 (0.6H, m), 1.89 (0.4H, m), 1.81 (0.6H, m), 1.70 (1H, m), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 161.8, 160.2, 160.2, 156.9, 156.8, 133.1, 133.1, 133, 132.4, 132.3, 130.8, 130.7, 129.2, 129.1, 129.1, 129, 118, 117.9, 116.2, 116.2, 116.2, 116.1, 69.4, 69.3, 67.2, 67.1, 56.6, 53, 52.4, 31.6, 31.6, 31.5, 31.5, 29.9, 29.8, 29.8, 29.4, 29.3, 22.1, 20.7.

Example 467: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.64 (1H, m), 7.21 (1H, br t, J=9.0 Hz), 5.11 (0.6H, m), 4.71 (0.4H, m), 4.11 (1H, br d, J=12.2 Hz), 4.0-3.51 (7H, m), 3.32 (3H, 2 s), 2.96 (1.8H, s), 2.76 (2.2H, m), 2.24 (0.4H, m), 2.12 (0.6H, m), 1.88 (0.4H, m), 1.80 (0.6H, m), 1.69 (1H, m), 1.26 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.9, 156.8, 156.2, 156.1, 130.4, 130.3, 130.3, 117.1, 116.9, 116.8, 116.6, 116.5, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 69.4, 69.3, 67.2, 67.1, 56.6, 53, 52.2, 31.5, 31.5, 29.9, 29.9, 29.8, 29.5, 29.3, 27.7, 25.7, 21.8, 21.7, 21.2, 21.2.

Example 468: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 7.45 (2H, m), 7.30 (1H, m), 5.11 (0.6H, m), 4.72 (0.4H, m), 4.15 (1H, br d, J=11.9 Hz), 4.0-3.52 (7H, m), 3.31 (3H, 2 s), 2.97 (1.8H, s), 2.86 (1H, m), 2.76 (1.2H, s), 2.24 (0.4H, m), 2.12 (0.6H, m), 1.89 (0.4H, m), 1.80 (0.6H, m), 1.70 (1H, m), 1.13 (1H, m).

¹³C NMR (DMSO_(d6)): 168.3, 167.7, 161.3, 161.3, 159.7, 159.7, 156.9, 156.8, 130.8, 130.7, 130.2, 130.2, 129.4, 129.4, 128.8, 128.7, 128.7, 128.6, 128.6, 128.3, 117.6, 117.4, 116.3, 116.2, 69.4, 69.3, 67.2, 67.1, 56.6, 53.1, 52.4, 31.7, 31.6, 31.5, 31.5, 30, 29.8, 29.8, 29.5, 29.3, 27.7, 22.1, 20.7.

Example 469: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d₃)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.11 (1H, d, J=7.5 Hz), 7.61 (1H, td, J=8.7, 5.6 Hz), 7.22 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.6, 9.2 Hz), 3.81 (3H, m), 3.74 (1H, m), 3.42 (2H, m), 3.33 (2H, m), 3.29 (1H, dd, J=9.0, 15.9 Hz), 2.89 (1H, dd, J=15.9, 8.0 Hz), 1.69 (2H, m), 1.38 (2H, m).

¹³C NMR (DMSO_(d6)): 166.8, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.6, 128.4, 118.8, 118.7, 118.6, 116.4, 116, 115.9, 113.2, 113.1, 65.8, 49.5, 45.2, 34.7, 32.4, 31.3, 29.2.

Example 470: R)-6-(2,3,6-trifluoropheny)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(2,3,6-trifluoropheny)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((R)-tetrahydrofuran-3-yl)acetamide and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.90 (1H, br s), 9.24 (2H, m), 7.49 (1H, m), 7.19 (1H, m), 4.43 (1H, quin, J=8.8 Hz), 4.16 (1H, dd, J=11.2, 9.0 Hz), 3.92 (1H, m), 3.88 (1H, m), 3.82 (1H, m), 3.75 (2H, m), 3.65 (1H, m), 3.32 (1H, dd, J=9.1, 15.5 Hz), 3.15 (2H, m), 2.96 (1H, br dd, J=15.6, 8.7 Hz), 2.81 (2H, br t, J=7.6 Hz), 2.20 (1H, m), 2.01 (1H, m).

¹³C NMR (DMSO_(d6)): 157, 156.9, 155.9, 155.4, 155.3, 150.9, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.3, 118.5, 118.5, 118.4, 118.3, 116.6, 116.5, 116.5, 116.4, 114.9, 112, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 68.8, 66.4, 57.3, 48.3, 43.7, 35.7, 29, 28.8, 21.2.

Example 471: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white powder.

¹H NMR (DMSO_(d6)): 11.81 (1H, br s), 7.84 (1H, m), 4.49 (1H, m), 4.15 (1H, dd, J=11.7, 9.1 Hz), 3.76 (1H, dd, J=11.7, 7.6 Hz), 3.29 (1H, dd, J=15.6, 9.3 Hz), 2.90 (1H, dd, J=15.7, 7.8 Hz), 2.38 (6H, m), 2.33 (2H, t, J=7.1 Hz), 1.66 (6H, m).

¹³C NMR (DMSO_(d6)): 155, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 127.4, 120.6, 120.5, 120.4, 119.6, 105.8, 105.7, 105.5, 54.6, 53.5, 48.3, 35.8, 29, 26.9, 23.1, 22.

Example 472: (R)-1-(3-(isopropylamino)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from (R)-N-isopropyl-3-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 11.85 (1H, br s), 8.44 (2H, br), 7.48 (1H, qd, J=9.4, 5.0 Hz), 7.18 (1H, m), 4.47 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.31 (1H, dd, J=9.5, 15.8 Hz), 3.25 (1H, m), 2.91 (1H, dd, J=15.6, 7.8 Hz), 2.84 (2H, m), 2.45 (2H, t, J=7.4 Hz), 1.83 (2H, quin, J=7.6 Hz), 1.19 (6H, d, J=6.6 Hz).

¹³C NMR (DMSO_(d6)): 156.9, 156.9, 155.4, 155.3, 155.3, 149.1, 149.1, 149, 149, 148.9, 147.6, 147.6, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 147.3, 147.3, 146, 145.9, 145.9, 145.9, 128.1, 119.1, 119, 119, 118.9, 118.2, 116.5, 116.5, 116.4, 116.4, 112, 112, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 49.5, 48.5, 43.2, 35.6, 29.1, 24.7, 21.2, 18.7, 18.6.

Example 473: (R)-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-N-((tetrahydro-2H-pyran-4-yl)methyl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide and isolated as a yellow solid.

¹H NMR (DMSO_(d6)): 11.91 (1H, s), 8.93 (2H, m), 7.50 (1H, m), 7.19 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.86 (2H, m), 3.75 (1H, dd, J=11.5, 8.3 Hz), 3.32 (1H, dd, J=15.5, 9.2 Hz), 3.27 (2H, td, J=11.7, 2.1 Hz), 3.12 (2H, m), 2.95 (1H, dd, J=15.6, 8.7 Hz), 2.82 (4H, m), 1.94 (1H, m), 1.67 (2H, m), 1.21 (2H, qd, J=12.2, 4.5 Hz).

¹³C NMR (DMSO_(d6)): 156.9, 156.9, 155.8, 155.3, 155.3, 129.2, 118.6, 118.5, 118.5, 118.4, 116.6, 116.5, 116.5, 116.4, 115, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 66.3, 51.9, 48.3, 45.4, 35.7, 31.7, 30, 29, 20.8.

Example 474: (R)-2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 9.65 (1H, m), 7.49 (1H, m), 7.19 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.3, 11.3 Hz), 3.82 (1H, dd, J=11.6, 7.9 Hz), 3.47 (3H, s), 3.38 (1H, dd, J=9.4, 15.7 Hz), 3.25-2.95 (6H, m), 3.00 (1H, dd, J=15.7, 8.2 Hz), 2.87 (2H, m), 1.89 (4H, m).

¹³C NMR (DMSO_(d6)): 156.9, 156.9, 156.5, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 145.8, 127.9, 118.8, 118.7, 118.7, 118.6, 117.4, 117.3, 116.5, 116.5, 116.4, 116.4, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 53.3, 51.8, 49.3, 34.8, 31.3, 29.3, 22.7, 21.6.

Example 475: (R)-1-(2-((((S)-tetrahydrofuran-2-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from N-(((S)-tetrahydrofuran-2-yl)methyl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide and isolated as a cream powder.

¹H NMR (DMSO_(d6)): 11.90 (1H, s), 8.92 (2H, m), 7.49 (1H, m), 7.19 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (2H, m), 3.80 (1H, dt, J=8.1, 6.9 Hz), 3.75 (1H, dd, J=11.6, 8.4 Hz), 3.71 (1H, td, J=7.8, 6.1 Hz), 3.30 (1H, dd, J=15.6, 9.1 Hz), 3.15 (2H, m), 3.06 (1H, m), 2.94 (1H, dd, J=8.6, 15.6 Hz), 2.89 (1H, m), 2.79 (2H, t, J=7.6 Hz), 2.00 (1H, m), 1.85 (2H, m), 1.55 (1H, m).

¹³C NMR (DMSO_(d6)): 157, 156.9, 155.8, 155.4, 155.3, 149.1, 149.1, 149.1, 149, 149, 149, 147.6, 147.6, 147.5, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.9, 129.2, 118.6, 118.5, 118.5, 118.4, 116.6, 116.5, 116.5, 116.4, 115, 112, 112, 112, 112, 111.9, 111.9, 111.8, 111.8, 73.7, 67.6, 50.3, 48.3, 45.3, 35.8, 29, 28.8, 25, 20.9.

Example 476: (R)-1-(2-(tert-butylamino)ethyl)-2-methyl-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from (R)-N-(tert-butyl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide and isolated as an off-white solid.

¹H NMR (DMSO_(d6)): 8.61 (2H, m), 7.50 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.8 Hz), 4.24 (1H, dd, J=9.5, 11.2 Hz), 3.83 (1H, dd, J=11.6, 8.2 Hz), 3.48 (3H, s), 3.42 (1H, dd, J=9.3, 15.5 Hz), 3.04 (1H, dd, J=8.5, 15.8 Hz), 3.02 (2H, m), 2.83 (2H, m), 1.25 (9H, br s).

¹³C NMR (DMSO_(d6)): 157, 156.5, 155.4, 149.2, 149.1, 147.6, 147.5, 147.5, 146.1, 146, 145.9, 128.1, 118.7, 118.6, 118.5, 117.2, 116.6, 116.5, 116.5, 116.4, 112, 111.8, 55.7, 49.3, 39.8, 34.8, 31.4, 29.1, 25.7, 22.2.

Example 477: (R)-2-methyl-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and isolated as a beige solid.

¹H NMR (DMSO_(d6)): 8.87 (2H, m), 7.49 (1H, m), 7.19 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.23 (1H, dd, J=11.4, 9.3 Hz), 3.85 (2H, m), 3.82 (1H, dd, J=11.7, 8.1 Hz), 3.47 (3H, s), 3.39 (1H, dd, J=9.3, 15.7 Hz), 3.28 (2H, td, J=11.7, 2.1 Hz), 3.12 (2H, m), 3.0 (1H, dd, J=8.3, 15.7 Hz), 2.97 (2H, m), 2.84 (2H, q, J=6.5 Hz), 1.94 (1H, m), 1.67 (2H, m), 1.22 (2H, qd, J=12.3, 4.8 Hz).

¹³C NMR (DMSO_(d6)): 157, 156.9, 156.6, 155.4, 155.3, 149.1, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.4, 147.4, 146, 145.9, 145.9, 145.9, 128.4, 118.7, 118.7, 118.6, 118.5, 116.7, 116.6, 116.6, 116.5, 116.4, 112.1, 112, 112, 112, 111.9, 111.9, 111.8, 111.8, 66.3, 52.1, 49.4, 45.2, 34.8, 31.9, 31.4, 30, 29.2, 20.8.

Example 478: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-3-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a light beige solid.

¹H NMR (DMSO_(d6)): 11.84 (1H, s), 9.83 (1H, m), 7.48 (1H, m), 7.19 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.4, 9.1 Hz), 3.74 (1H, dd, J=11.7, 8.1 Hz), 3.29 (1H, dd, J=9.0, 15.6 Hz), 3.19-2.86 (4H, br), 3.05 (2H, m), 2.93 (1H, dd, J=15.6, 8.4 Hz), 2.43 (2H, br t, J=7.5 Hz), 1.94 (6H, m).

¹³C NMR (DMSO_(d6)): 156.9, 156.9, 155.4, 155.3, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 128.1, 118.9, 118.8, 118.7, 118.7, 118.2, 116.6, 116.5, 116.4, 116.4, 112, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 53.2, 48.4, 35.7, 29, 24.2, 22.6, 21.2.

G. Dopamine-β-Hydroxylase Inhibition Assay

The ability of a compound to inhibit DβH activity may be assessed using the following cell assay. For the purposes of the present invention, a compound is considered to be a “DβH inhibitor” if it exhibits activity in “% of control” of <20% at 10 μM in this cell assay. Preferred compounds of the present invention (including almost all of the specific Examples above) exhibit activity in “% of control” of ≤50% at 1.0 μM in this cell assay. More preferred compounds of the present invention exhibit activity in “% of control” of ≤20% at 1.0 μM in this cell assay. Especially preferred compounds of the present invention exhibit activity in “% of control” of ≤50% at 100 nM in this assay.

SK-N-SH cells (ATCC HTB-11), obtained from LGC Standards (Teddington, UK) were cultured in Eagle's minimum essential medium supplemented with 25 mM Hepes, 100 U/mL penicillin G, 0.25 μg/mL amphotericin B, 100 μg/mL streptomycin and 10% Gibco© fetal bovine serum. Cells were grown in T162 cm flasks (Corning, N.Y.) in a humidified atmosphere of 5% CO₂-95% air at 37° C. Fetal bovine serum was removed from cells for 4 h prior to collection.

For the preparation of cellular homogenates, media was removed and cell monolayers were washed with 50 mM Tris-HCl pH 7.4. Cells were subsequently scraped off the flasks and were resuspended in 50 mM Tris pH 7.4. Cell suspensions were homogenized with SilentCrusher M (Heidolph) for a short stroke and resultant homogenates were aliquoted and stored frozen at −80° C.

Total protein was quantified in cellular homogenates with BioRad Protein Assay (BioRad) using a standard curve of BSA (50-250 μg/mL).

DβH activity was measured by a modification of the method of Nagatsu and Udenfriend (Nagatsu, T. and S. Udenfriend: “Photometric assay of dopamine-hydroxylase activity in human blood.” Clin. Chem. 18(9): 980-983, 1972) which is based on the enzymatic hydroxylation of tyramine into octopamine. The octopamine formed is subsequently oxidized to p-hydroxybenzaldehyde and measured by spectrophotometry. In brief, reaction mixture (total volume 500 μl) contained: cellular homogenate (75 μg total protein), sodium acetate pH 5.0 (200 mM), N-ethylmaleimide (30 mM), CuSO₄ (5 μM), catalase aqueous solution (0.5 mg/mL), pargyline-HCl (1 mM), sodium fumarate (10 mM), ascorbic acid (10 mM), inhibitor or vehicle and tyramine (25 mM). After a 10 min pre-incubation period at 37° C., the reaction was initiated by the addition of tyramine. Reaction was carried out for 45 min at 37° C. before termination with 50 μl perchloric acid (2 M). Samples were centrifuged for 3 min at 16100 g and supernatants were subjected to solid phase extraction. Solid phase extraction was performed using either SPE cartridges ISOLUTE SCX-3 (100 mg, 1 mL) or SPE 2 mL fixed 96 well plates ISOLUTE SCX-3 (100 mg) previously equilibrated with MilliQ water. Columns/plates were centrifuged at 150 g for 2 min. Eluate was discarded and matrix was washed with 1 mL of MilliQ water after which octopamine was eluted with 2×0.25 mL ammonium hydroxide (4 M). The oxidation of octopamine to p-hydroxybenzaldehyde was carried out for 6 min with 100 μl sodium periodate (2%) and was stopped with 100 μl sodium metabisulfite (10%). Absorbance was measured at 330 nm on a Spectramax microplate reader (Molecular Devices, Sunnyvale, Calif.). All enzymatic reactions were performed in duplicate.

Results are reported in the table below as activity in % of control at the inhibitor concentration tested.

Furthermore, the ability of a compound to inhibit DβH activity may be assessed in human plasma using the following assay. For the purposes of the present invention, a compound is considered to be a “DβH inhibitor” if it exhibits activity in “% of control” of ≤20% at 10 μM in this assay. Preferred compounds of the present invention (including most of the specific Examples above) exhibit activity in “% of control” of ≤50% at 1.0 μM in this cell assay. More preferred compounds of the present invention exhibit activity in “% of control” of ≤20% at 1.0 μM in this cell assay. Especially preferred compounds of the present invention exhibit activity in “% of control” of ≤50% at 100 nM in this assay.

Dopamine beta hydroxylase activity in human plasma was measured by the method of Nagatsu and Udenfriend (Nagatsu, T. and Udenfriend, S. “Photometric assay of dopamine-p-hydroxylase activity in human blood.” Clin. Chem. 18(9) 980-983, 1972) with minor modifications. Catalase, N-ethylmaleimide, tyramine, disodium fumarate, pargyline, sodium acetate, ascorbic acid, copper sulfate and octopamine were obtained from Sigma Chemical Co., St. Louis, Mo. 63178. Human plasma samples were obtained from healthy donors (Instituto Portugues do Sangue Transplantagio, Centro Sangue Transplantagio, Porto, Portugal). From date of collection, plasma was stored at −80° C. until use. Test compounds were initially prepared in dimethyl sulfoxide at a concentration of 10 mM and diluted in dimethyl sulfoxide to the required concentrations. Test compounds were further diluted in ultrapure water to a concentration 20-fold to that of the final concentration to be tested. Final concentrations of test compounds were 10, 100 and 1000 nM. The various reagents used to make up the incubation buffer were premixed and consisted of the following components: sodium acetate buffer (1 M, pH 5.0, 18 ml), sodium fumarate (0.2 M, 4.5 ml), ascorbic acid (0.2 M, 4.5 ml, freshly prepared), pargyline (20 mM, freshly prepared, 4.5 ml), N-ethylmaleimide (0.2 M, 4.5 ml), catalase (10 000 U/ml, 9 ml), copper sulfate (20 PM, 4.5 ml) and 4.5 ultrapure water. The standard incubation mixture (total volume, 950 μl) contained: 50 μL of compound or vehicle (dimethyl sulfoxide 2%); 700 μL of incubation buffer; 125 μl of plasma (or saline for blank reaction or standard curve); 75 μl of saline. The reaction mixture was placed in water bath, shaking at 37° C. and pre-incubated for 10 minutes. Tyramine (0.5 M) was added and incubation proceeded for 45 minutes. The reaction contents were exposed to air. A sample of enzyme preparation (with 125 μl of plasma) that had been added perchloric acid 2 M at the end of the pre-incubation period was used as blank. A blank for each of the tested compounds was used. For octopamine standard curve, perchloric acid 2 M was replaced by increasing concentrations of octopamine prepared in perchloric acid 2 M (0.5, 1, 2.5, 5, 7.5, 10, 15, 20 μg/ml, final concentration). The incubation was stopped by adding 200 μl of 2 M molar perchloric acid, and the mixture was centrifuged at 9000 g for 5 min. The supernatant fluid (800 μL) was transferred to a column (SPE cartridge ISOLUTE SCX-3, 100 mg) and centrifuged at 150 g for 2 min. The column was washed two more times with 0.5 ml of ultrapure water by centrifuging at 150 g for 2 min. The adsorbed octopamine was eluted twice with 0.3 ml of 4 M ammonium hydroxide by centrifuging at 150 g for 2 min. Octopamine in the eluate was then converted to p-hydroxybenzaldehyde by adding 200 μl of sodium periodate (2%) and incubating for 6 min. Excess periodate was than reduced by adding 200 μl of sodium metabisulfite (10%). Absorbance was measured at 330 mm in a 96-well plate by use of a SpectraMAX plus 384 (Molecular Devices) with software SOFTmax® PRO Software 5.3 spectrophotometer. Absorbance was linear with octopamine concentration from 0.5 to 20 μg/ml. Dopamine beta hydroxylase activity is determined as nmol of octopamine formed/ml of plasma/hour and effect of compounds is presented as % control.

Results are reported in the table below as activity in % of control at the inhibitor concentration tested.

H. Evaluation of Pharmacokinetic Profile

Adult male Wistar rats were kept under controlled environmental conditions (12 h light/dark cycle, room temperature 22±1° C. and humidity 50±5%, food and tap water ad libitum). On the day before the experiment, the animals were fasted. In experiments designed to evaluate the pharmacokinetic profile of Examples 56, 66, 199 and 232, rats (n=4) were administered orally (p.o.) with examples 56, 66, 199 and 232 (10 mg/kg/4 mL; vehicle: 40% kleptose) and plasma and brain samples were collected from anaesthetized animals at 1 and 2 h post-dosing. Animals were anaesthetized by intraperitoneal administration of sodium pentobarbital (60 mg/kg). Blood was collected from cardiac punction into heparinised tubes and kept on ice until centrifugation at 1,500 g for 15 min at 4° C. Plasma and brain samples were stored at less than −20° C. until analysis.

After thawing, 200 μL of acetonitrile 0.1% formic acid was added to 100 μL of plasma. The samples were vortexed and centrifuged for 10 min at 10 000 g. Supernatant was filtered and injected into a mass spectrometer.

After thawing and weighing, water was added to the brain to give a tissue concentration of 0.1 mg/ml. The samples were then homogenized using a Heidolph DIAX 900 mixer and transferred to plastic tubes. Following centrifugation at 10 000 g for 20 min, supernatant was taken and treated as described for plasma.

I. DβH Activity in Rat Adrenal Gland Homogenates

Dopamine beta hydroxylase activity in rat adrenal gland homogenates was measured by the method of Nagatsu and Udenfriend (Nagatsu, T. and Udenfriend, S. “Photometric assay of dopamine-β-hydroxylase activity in human blood.” Clin. Chem. 18(9) 980-983, 1972) with minor modifications. Catalase, N-ethylmaleimide, tyramine, disodium fumarate, pargyline, sodium acetate, ascorbic acid, copper sulfate and octopamine were obtained from Sigma Chemical Co., St. Louis, Mo. 63178. Test compounds were prepared in kleptose 40% at a concentration of 0.75, 2.5 or 7.5 mg/mL to be administered at a dose of 10 mg/kg. Compounds and vehicle (kleptose 40%) were administered to wistar rats and adrenals were collected 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 15 h and 24 h after administration. Samples were constituted by the right and left adrenals of each animal. Adrenals were stored in 200 μL of 50 mM Tris pH 7.4 at −30° C., from date of collection. The samples were homogenized and homogenates were then quantified for protein. Protein concentration was adjusted to 1.6 mg/ml. The various reagents used to make up the incubation buffer were premixed and consisted of the following components: sodium acetate buffer (1 M, pH 5.0, 6.0 mL), sodium fumarate (0.2 M, 1.5 mL), ascorbic acid (0.2 M, 1.5 mL, freshly prepared), pargyline (20 mM, freshly prepared, 1.5 mL), N-ethylmaleimide (0.2 M, 1.5 mL), catalase (55 000 U/ml, 3 mL), copper sulfate (90 μM, 1.67 mL) and ultrapure water (1.33 mL). The standard incubation mixture (total volume, 500 μL) contained: 350 μL of incubation buffer; 125 μL of protein sample (or buffer for blank reaction or standard curve). The reaction mixture was placed in water bath with shaking at 37° C. and pre-incubated for 10 minutes. Tyramine (0.4 M, 25 μL) was added and incubation proceeded for 45 minutes. The reaction contents were exposed to air. A sample of enzyme preparation (with 125 μL of protein sample) that had been added perchloric acid 2 M at the end of the pre-incubation period was used as blank. A blank for each of the tested compounds was used. For octopamine standard curve, perchloric acid 2 M was replaced by increasing concentrations of octopamine prepared in perchloric acid 2 M (0.5, 1, 2.5, 5, 7.5, 10 μg/mL, final concentration). The incubation was stopped by adding 50 μL of 2 M molar perchloric acid, and the mixture was centrifuged at 16000 g for 3 min. The supernatant fluid (500 μL) was transferred to a column (SPE cartridge ISOLUTE SCX-3, 100 mg) and centrifuged at 150 g for 2 min. The column was washed two more times with 0.5 ml of ultrapure water by centrifuging at 150 g for 2 min. The adsorbed octopamine was eluted twice with 250 μL of 4 M ammonium hydroxide by centrifuging at 150 g for 2 min. Octopamine in the eluate was then converted to p-hydroxybenzaldehyde by adding 100 μL of sodium periodate (2%) and incubating for 6 min. Excess periodate was than reduced by adding 100 μl of sodium metabisulfite (10%). Absorbance was measured at 330 mm in a 96 well plate by use of a SpectraMAX plus 384 (Molecular Devices) with software SOFTmax® PRO Software 5.3 spectrophotometer. Absorbance was linear with octopamine concentration from 0.5 to 10 μg/mL. Dopamine beta hydroxylase activity is determined as nmol of octopamine formed/mg of protein/hour and effect of compounds is presented as % of control.

J. Catecholamine Determination

Catecholamines quantification in brain stem was performed as previously described (Bonifacio, M. J.; Sousa, F.; Neves, M.; Palma, N.; Igreja, B.; Pires, N. M.; Wright, L. C.; Soares-da-Silva, P. “Characterization of the interaction of the novel anthyhypertensive etamicastat with human dopamine-beta-hydroxylase: comparison with nepicastat.” Eur. J. Pharmacol. 751, 50-58, 2015.) with minor modifications. Test compounds were prepared in 40% of kleptose at a concentration of 2.5 mg/ml to be administered at a dose of 10 mg/kg. Compounds and vehicle (kleptose 40%) were administered to Wistar rats and tissues (brain stem or heart left ventricle) collected in perchloric acid (0.2M) at defined time points after administration. Tissues were stored overnight at 4° C. and the solution was then filtered by centrifugation (1500 g, 4 min, 4° C.) through 0.22 μm pore size filters (Costar Spin-x from Corning Inc., USA). Catecholamines were quantified in filtrates by directly injecting 50 μl of sample volume on a HPLC system with electrochemical detection, using a Spheri-5RP-185 mm column (Perkin-Elmer). Mobile phase consisted of a solution containing 0.1M citric acid, 0.1M sodium acetate, 0.15 mM EDTA, 1 mM dibutylamine, 1 mM octylsulfate, and 5% methanol adjusted to pH 3.5 with perchloric acid.

K. Biological Data

TABLE 1 The following table shows DβH inhibition in human SKNSH cell line and human plasma for the compounds: SKNSH SKNSH Plasma Plasma Plasma Example (1 μM) (0.1 μM) (1 μM) (0.1 μM) (0.01 μM) 1 37.9 2 49.3 3 35.8 4 20.3 5 19.9 6 3.7 36.9 7 3.6 45.6 8 15.3 9 54.9 10 2.1 46.4 11 28.5 12 3.3 30.8 13 13.9 68.0 14 45.6 92.8 15 11.4 66.0 16 12.7 72.9 17 32.2 79.0 18 19.8 81.0 19 16.4 20 2.6 31.0 21 16.7 69.2 22 4.4 45.1 23 8.8 56.6 24 45.6 100.2 25 17.6 71.3 26 18.2 64.0 27 7.6 51.6 28 33.8 78.1 29 29.1 72.5 30 73.2 92.0 31 16.7 67.7 32 9.7 46.2 33 33.4 34 0 10.4 35 45.9 36 50.1 37 15.7 38 20.9 39 29.8 40 29.3 41 60.7 42 8.0 51.5 43 45.6 44 45.9 45 46.8 46 4.3 41.5 47 62.9 48 48.4 49 33.7 50 1.8 57.5 51 0 0.4 0 5.7 52 0.2 9.2 1.6 10.3 53 0 13.4 2.7 26.2 54 4.2 33.8 3.4 32.2 55 3.9 48.9 11.1 62.1 56 5.2 45.6 5.5 38.5 57 0.2 11.6 0.1 18.1 58 9.3 56.8 14.0 59.2 59 4.1 20.8 60 14.0 68.9 61 47.9 99.1 62 10.9 66.4 63 11.9 58.3 64 47.2 88.4 65 12.6 64.5 66 6.4 52.3 67 13.2 76.1 68 13.5 55.6 69 24.1 82.1 70 2.9 36.6 71 11.9 57.0 72 28.9 90.8 73 19.1 75.9 74 8.1 70.3 75 56.3 91.0 76 13.1 65.8 77 38.9 87.2 78 24.4 77.3 79 10.3 54.3 80 9.8 60.7 81 15.9 63.1 82 16.6 69.2 83 15.9 78.8 84 1.0 24.5 85 12.2 59.1 86 14.7 70.9 87 13.8 62.8 88 6.1 44.1 89 0 4.3 90 0.4 9.9 91 0 19.0 92 0.1 37.5 93 1.0 32.1 94 0.8 47.5 95 0 24.0 96 0.8 22.4 97 0.5 22.7 98 11.7 53.1 99 10.3 55.7 100 2.1 26.2 101 3.3 37.2 102 1.7 20.3 103 1.8 21.6 104 19.5 67.9 105 22.0 74.9 106 4.1 33.9 107 6.3 40.1 108 5.3 46.9 109 1.5 5.4 110 9.7 52.4 111 36.7 89.6 112 0 9.9 113 25.6 85.1 114 7.5 58.4 115 0 48.0 116 68.8 93.8 117 43.0 74.5 118 49.0 89.2 119 87.7 118.2 120 86.2 132.5 121 62.6 79.3 122 13.0 70.8 123 6.3 51.9 124 3.3 42.8 125 43.7 106.5 126 40.2 100.2 127 83.8 81.3 128 29.7 98.1 129 10.3 50.1 130 8.4 55.7 131 50.5 89.8 132 62.3 91.9 133 82.4 95.9 134 3.2 24.9 135 58.1 88.3 136 6.8 44.3 137 21.5 72.9 138 5.0 46.6 139 20.8 77.8 140 26.8 73.1 141 76.1 93.2 142 16.2 60.0 143 0.2 20.1 144 0.1 14.7 145 2.0 18.2 146 0.9 13.8 147 2.4 29.0 148 0.9 17.1 149 3.0 52.5 150 17.1 64.8 151 20.2 73.7 152 17.8 72.1 153 28.4 85.5 154 38.6 89.5 155 19.7 91.5 156 40.3 88.6 157 24.2 84.2 158 52.1 90.9 159 50.9 84.3 160 50.8 84.7 161 46.0 85.0 162 31.3 87.2 163 2.4 14.8 164 17.1 65.8 165 14.8 74.3 166 14.1 66.9 167 3.2 28.0* 50.8 78.0* 168 10.5 51.9 169 17.1 59.3 170 2.0 64.9 171 3.7 40.4 172 8.1 46.3 173 33.1 94.2 174 8.5 52.7 175 13.8 61.7 176 74.9 95.3 177 77.1 99.9 178 29.5 88.2 179 48.8 93.5 180 22.3 99.2 181 18.3 68.9 182 71.0 94.6 183 79.8 92.2 184 43.7 89.2 185 30.9 72.9 186 18.0 62.7 187 21.6 72.6 188 15.4 60.9 189 23.2 87.4 190 19.9 68.6 191 26.0 82.3 192 12.1 73.4 193 46.3 86.0 194 62.4 82.9 195 41.7 77.3 196 68.6 102.2 197 29.4 75.9 198 11.1 99.1* 52.2 84.5* 199 0.6 84.9* 27.4 119.3* 200 66.4 85.2 201 13.3 62.4 202 22.7 67.7 203 75.8 95.8 204 1.1 26.5 205 18.2 76.9 206 8.7 22.4 207 30.2 76.6 208 13.3 62.0 209 60.3 87.6 210 73.5 94.6 211 94.8 104.9 212 46 86.5 213 66.6 105.9 214 72.1 109.1 215 34.2 74.3 216 47.1 84.5 217 92.3 99.8 218 69.1 89.2 219 19.7 69.9 220 17.7 76.5 221 30.0 79.3 222 12.9 73.6 223 7.2 42.7 224 0.6 22.6 225 12.5 65.3 226 47.4 100.8 227 54.9 86.8 228 56.0 90.2 229 38.3 84.3 230 41.6 82.0 231 5.6 35.9 232 6.4 48.8 233 66.8 9.7* 83.8 59.3* 234 12.2 43.4 235 1.2 11.4 236 51.0 104.2 237 61.6 92.9 238 88.5 93.4 239 3.9 60.1 240 39.2 76.1 241 8.9 51.7 242 53.6 91.5 243 4.4 37.6* 38.0 87.3* 244 32.9 83.6 245 93 107.8 246 80.3 115.2 247 35.9 81.7 248 51.8 98.2 249 40.9 96.0 250 7.3 46.1 251 36.0 80.0 252 54.8 6.7* 82.2 46.0* 253 24.5 63.4 254 62.2 81.4 255 24.6 71.8 256 29.2 61.7 257 92.4 105.9 258 21.3 84.2 259 76.1 90.8 260 26.5 84.1 261 31.8 86.2 262 70.1 82.6 263 87.1 103.3 264 54.2 98.4 265 70.6 94.9 266 56.0 85.3 267 55.8 90.8 268 57.7 99.8 269 83.7 105.6 270 53.8 88.1 271 13.2 62.1 272 22.7 73.5 273 28.9 86.6 274 11.2 55.9 275 24.4 79.0 276 33.3 83.3 277 3.4 35.4 278 62.0 84.2 279 15.7 61.7 280 51.4 92.8 281 29.8 107.9 282 75.4 99.6 283 72.9 96.0 284 41.9 84.8 285 22.2 55.8 286 3.4 73.8 287 15.5 66.8 288 81.1 82.0 289 58.3 87.1 290 3.8 37.6 291 1.7 30.2 292 68.3 101.9 293 86.0 104.8 294 1.7 39.7 295 71.5 95.6 296 74.5 89.2 297 35.4 78.7 298 28.2 83.5 299 48.4 84.3 300 10.9 57.0 301 6.4 49.1 302 7.7 62.7 303 34.7 79.3 304 21.1 51.9 305 12.2 61.2 306 18.0 70.6 307 33.0 73.9 308 12.8 64.2 309 38.8 86.2 310 22.3 65.9 311 21.6 87.2 312 51.7 15.0* 84.8 67.6* 313 9.6 37.6 314 34.8 1.4* 80.2 41.9* 315 17.0 53.3* 67.0 94.0* 316 4.5 16.6* 43.4 73.1* 317 5.3 45.6 318 61.4 88.4 319 16.5 67.9 320 31.1 90.3 321 13.3 89.7 322 43.4 62.3 323 43.3 86.3 324 53.1 88.6 325 3.8 34.2 326 59.5 96.6 327 7.0 49.9 328 9.4 63.1 329 16.1 41.7 330 32.5 71.7 331 50.2 77.4 332 2.7 32.8 333 11.7 47.5 334 41.9 80.3 335 8.7 44.9 336 9.4 50.0 337 9.4 48.2 338 6.2 36.4 339 4.3 42.3 340 27.0 87.6 341 33.6 91.1 342 16.5 66.6 343 59.5 94.9 344 73.7 88.2 345 40.3 77.2 346 74.9 109.6 347 17.7 79.0 348 44.8 92.4 349 12.5 72.3 350 28.2 85.7 351 16.5 46.2 352 10.9 40.8 353 38.4 90.6 354 53.4 106.2 355 14.0 56.4 356 6.6 35.4 357 15.1 62.1 358 24.9 90.1 359 53.3 101.2 360 1.4 22.5* 31.8 90.1* 361 10.4 60.0 362 11.8 43.2 363 20.8 89.5 364 54.7 97.0 365 56.9 101.3 366 81.4 124.8 367 4.3 45.4 368 63.1 104.4 369 60.1 86.0 370 64.7 88.5 371 17.7 79.0 372 32.0 93.4 373 12.8 66.1 374 50.0 97.4 375 40.7 90.0 376 59.3 116.3 377 56.8 102.0 378 52.6 110.2 379 50.1 108.7 380 27.4 74.9 381 3.2 30.0 382 6.0 37.6 383 14.8 65.6 384 43.4 104.5 385 19.3 68.1 386 79.4 101.8 387 43.7 92.9 388 71.1 80.8 389 33.1 75.2 390 52.0 75.0 391 40.7 83.8 392 13.2 62.3 393 65.7 90.6 394 47.6 92.1 395 47.8 96.9 396 10.8 66.9 397 24.1 79.9 398 23.0 94.3 399 4.0 40.6 400 7.3 31.9 401 35.2 66.5 402 20.9 59.6 403 4.8 29.9 404 26.2 78.7 405 4.5 50.7 406 2.8 28.9 407 42.3 102.6 408 14.7 77.0 409 64.4 112.6 410 11.1 62.3 411 78.6 104.2 412 63.2 106.2 413 3.1 42.4 414 49.0 95.4 415 2.1 14.9 416 25.4 75.3 417 60.5 87.7 418 3.0 27.7 419 61.0 92.5 420 48.5 87.8 421 5.8 26.1 422 23.2 68.1 423 1.7 18.5 424 20.6 59.5 425 52.0 78.6 426 66.3 83.5 427 34.2 78.1 428 32.3 68.2 429 5.8 37.8 430 2.2 25.3 431 10.1 54.3 432 43.7 79.7 433 9.2 56.9 434 8.5 52.5 435 36.6 66.5 436 23.9 73.6 437 6.1 62.7 438 7.5 64.0 439 11.8 67.2 440 8.4 57.2 441 37.4 72.8 442 10.0 43.6 443 11.5 59.2 444 57.7 73.5 445 73.7 95.1 446 62.9 83.0 447 33.2 94.4 448 65.3 93.3 449 2.3 27.8 450 2.3 32.6 451 5.5 39.8 452 12.8 49.6 453 10.4 56.6 454 8.1 56.8 455 50.2 131.0 456 20.2 86.8 457 7.3 42.1 458 12.2 58.5 459 13.5 65.6 460 18.2 43.9 461 6.9 45.6 462 10.3 50.2 463 3.7 29.1 464 4.5 33.4 465 9.0 62.3 466 6.5 49.6 467 4.0 27.9 468 13.1 65.8 469 1.5 33.7 470 79.4 112.0 472 14.2 63.3 473 46.2 98.9 474 79.3 92.5 475 67.0 85.0 476 64.8 94.3 477 59.4 84.6 478 5.1 46.7 *Compound was re-tested under the same experimental conditions. It is believed that the difference between the previously generated data and the retest data is due to human error. Asterisked data are believed to be correct.

TABLE 2 The following table shows plasma (C_(pl)) and brain (C_(br)) concentrations (10 mg/kg, rat, po) for the examples 56, 66, 199 and 232: C_(pl) (ng/mL) C_(pl) (ng/mL) C_(br) (ng/g) C_(br) (ng/g) Example at 1 h at 2 h at 1 h at 2 h 56 1498 1128 20 21 66 779 429 0 0 199 1642 777 45 0 232 1712 1311 24 46

As can be seen from the table above, the examples 56, 66, 199 and 232 are peripherally selective, i.e. they exhibit significantly greater exposure in plasma compared to brain.

TABLE 3 The following table shows the maximal DβH activity in rat adrenal gland homogenates (ADR) (within a period of 6 h post-dose) and levels of noradrenaline (NA) in brain stem (Br.s) (15 h post-dose) after oral administration of 10 mg/kg of compounds of Examples 174, 191, 195, 219, 231, 256, and 403. Each experiment represents mean ± SD of 4 rats. Example DβH activity in ADR (% Control) NA in Br.s (% Control) 174 39 ± 18 84 ± 8  191 45 ± 8  83 ± 10 195 21 ± 9  123 ± 55  219 43 ± 16 92 ± 23 231 43 ± 9  99 ± 14 256 44 ± 22 128 ± 64  403 0 ± 0 87 ± 16

The above table shows that examples 174, 191, 195, 219, 231, 256 and 403 inhibit D (3H at a dose of 10 mg/kg in peripheral tissues such as ADR. Furthermore, they failed to reduce levels of NA in CNS tissues such as in brain stem, suggesting that the compounds are peripherally selective. 

1. A method for treating or preventing conditions ameliorated by inhibition of dopamine-beta-hydroxylase outside the central nervous system comprising administering a therapeutically effective amount of a compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof,

wherein: R₁ is hydrogen, C₁-C₆ alkyl, partially or fully deuterated C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₄ is hydrogen or C₁-C₃ alkyl; R is hydrogen; or R₄ and R combine, together with the carbon atoms to which they are attached, to form a cyclopropyl ring; R₆ is —COOH, —CHO, or —(CH₂)_(m)—X, wherein: m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

X is hydroxy, C₁-C₃ alkoxy, cyano, —N═CH(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl optionally substituted with one methyl group, phenyl, —SO₂—R₇, —NR₈R₉, —CO₂R₁₀, —CH(CO₂R₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄; wherein: R₇ is C₁-C₃ alkyl; R₈ is hydrogen or C₁-C₃ alkyl; R₉ is hydrogen, C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, C₃-C₆ cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; or R₈ and R₉ combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or with one or two substituents selected from fluoro and oxo, or a 9- or 10-membered heterospirocyclyl group; R₁₀ is hydrogen or C₁-C₃ alkyl; R₁ is hydrogen or C₁-C₃ alkyl; R₁₂ is hydrogen, C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of cyano, hydroxy, methylsulfonyl, C₁-C₂ alkoxy, dimethylamino, C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heteroaryl optionally substituted with one methyl substituent and 5- or 6-membered heterocyclyl optionally substituted with one t-Boc group or with one or two fluoro substituents, C₃-C₆ cycloalkyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxy, hydroxymethyl and oxo, cyano, methylsulfonyl, CH₂COO(C₁-C₃ alkyl), 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl, CH₂CH(NH₂)(COOH), or CH(CH₃)CONH₂; or R₁₁ and R₁₂ combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo, or optionally fused to a cyclopropyl ring which may be substituted with one or two methyl substituents, or a 9- or 10-membered heterospirocyclyl group; R₁₃ is hydrogen or C₁-C₃ alkyl; R₁₄ is C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃-C₆ cycloalkyl and phenyl, C₃-C₆ cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; A is C₅-C₇ cycloalkyl, furanyl, thiophenyl, methylthiophenyl or

wherein: X₁ is hydrogen, halo or methyl; X₁′ is hydrogen or halo; X₂ is hydrogen, halo or methyl; X₂′ is hydrogen or halo; X₃ is hydrogen or fluoro; n is 0 or 1, and when n is 0 a single bond joins the carbon atoms to which the CH₂ moiety would be attached when n is
 1. 2. A compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof:

wherein: R₁ is hydrogen, C₁-C₆ alkyl, partially or fully deuterated C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₄ is hydrogen or C₁-C₃ alkyl; R₅ is hydrogen; or R₄ and R combine, together with the carbon atoms to which they are attached, to forma cyclopropyl ring; R₆ is —COOH, —CHO, or —(CH₂)_(m)—X, wherein: m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

X is hydroxy, C₁-C₃ alkoxy, cyano, —N═CH(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl optionally substituted with one methyl group, phenyl, —SO₂—R₇, —NR₈R₉, —CO₂R₁₀, —CH(CO₂R₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄; wherein: R₇ is C₁-C₃ alkyl; R₈ is hydrogen or C₁-C₃ alkyl; R₉ is hydrogen, C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, C₃-C₆ cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; or R₈ and R₉ combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or with one or two substituents selected from fluoro and oxo, or a 9- or 10-membered heterospirocyclyl group; R₁₀ is hydrogen or C₁-C₃ alkyl; R₁₁ is hydrogen or C₁-C₃ alkyl; R₁₂ is hydrogen, C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of cyano, hydroxy, methylsulfonyl, C₁-C₂ alkoxy, dimethylamino, C₃-C₆ cycloalkyl, phenyl, 5- or 6-membered heteroaryl optionally substituted with one methyl substituent and 5- or 6-membered heterocyclyl optionally substituted with one t-Boc group or with one or two fluoro substituents, C₃-C₆ cycloalkyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxy, hydroxymethyl and oxo, cyano, methylsulfonyl, CH₂COO(C₁-C₃ alkyl), 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl, CH₂CH(NH₂)(COOH), or CH(CH₃)CONH₂; or R₁₁ and R₁₂ combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo, or optionally fused to a cyclopropyl ring which may be substituted with one or two methyl substituents, or a 9- or 10-membered heterospirocyclyl group; R₁₃ is hydrogen or C₁-C₃ alkyl; R₁₄ is C₁-C₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃-C₆ cycloalkyl and phenyl, C₃-C₆ cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; A is C₅-C₇ cycloalkyl, furanyl, thiophenyl, methylthiophenyl or

wherein: X₁ is hydrogen, halo or methyl; X₁′ is hydrogen or halo; X₂ is hydrogen, halo or methyl; X₂′ is hydrogen or halo; X₃ is hydrogen or fluoro; n is 0 or 1, and when n is 0 a single bond joins the carbon atoms to which the CH₂ moiety would be attached when n is
 1. 3. The method according to claim 1, wherein n is
 0. 4. The method according to claim 1, wherein R₄ and R₅ combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring.
 5. The method according to claim 1, wherein more than 50% of substituents R₅ and A have the stereochemical configuration of formula Id,


6. The method according to claim 1, wherein more than 50% of substituents R₅ and A have the stereochemical configuration of formula Ie,


7. The method according to claim 1, wherein A is

wherein X₁, X₁′, X₂, X₂′ and X₃ are as defined in claim
 1. 8. The method according to claim 1, wherein R₁ is hydrogen, methyl or d₃-methyl.
 9. The method according to claim 1, wherein R₄ is hydrogen or methyl.
 10. The method according to claim 1, wherein R₅ is hydrogen.
 11. The method according to claim 1, wherein R₆ is —COOH, —CHO, or —(CH₂)_(m)—X, wherein: m is 1, 2 or 3 and one —CH₂— moiety within —(CH₂)_(m)— may optionally be replaced by

X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH₂), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO₂—R₇, —NR₈R₉, —COOR₁₀, —CH(COOR₁₀)₂, —CONR₁₁R₁₂ or —NR₁₃COR₁₄; wherein: R₇ is methyl; R₈ is hydrogen or methyl; R₉ is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (tetrahydrofuran-2-yl)methyl, (1,1-dioxido)tetrahydrothiopyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, pyridin-2-yl, pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl, (pyridin-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R₈ and R₉ combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R₁₀ is hydrogen, methyl or ethyl; R₁₁ is hydrogen or methyl; R₁₂ is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH₂COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH₂CH(NH₂)(COOH), CH(CH₃)CONH₂, oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl, (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl, thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl, 1-methylpyrazol-4-yl, isothiazol-4-yl, 1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-methyl-5-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl; or R₁₁ and R₁₂ combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-(fluoromethyl)pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, N,N-dimethylpyrrolidinyl-3-carboxamide, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N,N-dimethylpiperidinyl-4-carboxamide, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl, 3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl, 2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl, 3-fluoromethylpyrrolidinyl or 3-(N,N-dimethylacetamide)pyrrolidinyl; R₁₃ is hydrogen or methyl; R₁₄ is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl.
 12. The method according to claim 1, wherein A is

wherein: X₁ is hydrogen, fluoro, chloro or methyl; X₁′ is hydrogen, fluoro or chloro; X₂ is hydrogen, fluoro, chloro, bromo or methyl; X₂′ is hydrogen, fluoro, chloro or bromo; X₃ is hydrogen or fluoro.
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. (canceled)
 17. The method according to claim 1, with the proviso that the compound (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione is excluded.
 18. The method according to claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof. 